Summary of experimental literature review.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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The phenomenon of condensation heat transfer has been researched for over a century now. In the beginning, the primary focus to increase heat transfer was kept limited to the increase in surface area. Later, it was revealed that surface‐tension forces play a vital role in thinning the condensate layer which in turn increases heat transfer. The mechanism of condensation heat transfer on two‐dimensional integral‐fin tubes is now well understood. Researchers have successfully identified the optimum geometries, fin shapes, dimensions and materials for integral‐fin tubes for a wide range of condensing fluids. A number of theoretical models, for instance Briggs and Rose [1], Ali and Briggs [2], have successfully combined the effect of surface tension and gravity to explain condensation heat transfer on integral‐fin and pin‐fin tubes. However, relatively fewer investigations have been carried out for condensation on three‐dimensionally enhanced tubes.
This chapter presents a state‐of‐the‐art review of condensation heat transfer on single‐horizontal geometrically enhanced tubes. The problem of condensate retention on geometrically enhanced tubes has been reviewed in detail followed by the experimental and theoretical investigations of condensation heat transfer on integral‐finned and pin‐finned tubes.
The first investigator to propose a theoretical model of condensation heat transfer on vertical plates and horizontal tubes was Nusselt [3]. By considering laminar flow and constant properties for the condensate film, uniform temperature on the vapour side (no temperature gradient in the vapour), and neglecting inertia, convection in the condensate film (i.e. heat transfer across the condensate film occurs only by conduction) and shear stress at the condensate surface, the following results were obtained:
For a vertical plate:
For a horizontal tube:
Many theoretical investigations have since been carried out including factors neglected by Nusselt [3] such as convection in condensate, shear stress and inertia (for instance, Sparrow and Gregg [4], Koh et al. [5] and Chen [6, 7]). The inclusion of these parameters made little practical difference to the results of Nusselt [3]. Rose [8] reports a comprehensive literature review of theoretical studies of laminar‐film condensation on smooth tubes.
It is well understood that heat‐transfer rate is strongly influenced by the available area. For that reason, a long time ago smooth tubes were replaced by horizontal integral‐fin tubes. No doubt, the addition of the fins provides an increase in area that ultimately leads to an enhancement in heat transfer, but a significant amount of condensate is retained on the tube due to capillary forces. This phenomenon of trapped liquid between fins is known as ‘condensate retention or flooding’ and is illustrated in Figure 1. This condensate offers a great resistance to heat transfer. A flooding angle,
Condensate flooding on a horizontal integral‐fin tube showing retention angle ∅f.
Rudy and Webb [10, 11] reported experimental investigations of condensate retention on three integral‐fin tubes and a spine‐fin tube with fin densities in a range of 748–1378 fins per meter using n‐pentane, R‐11 and water under static (without condensation) and dynamic (with condensation) conditions. For all the fluids, they found an increase in condensate retention with increasing fin density and surface‐tension‐to‐density ratio. They also found no significant differences in condensate retention under static and dynamic conditions.
Honda et al. [12] presented a comprehensive experimental and theoretical analysis of condensate flooding using R‐113 and methanol on three horizontal integral‐fin tubes and a saw‐toothed tube with and without ‘drainage strips’. A significant decrease in condensate retention was reported when the same tubes were used with drainage strips. One of the integral‐fin tubes was tested under both static and dynamic conditions and no significant change in condensate retention was observed which was in line with the findings of Rudy and Webb [10].
Honda et al. [12] made the following assumptions for their theoretical analysis of the static meniscus between trapezoidal fins:
The meniscus is just in contact with the fin tip.
The radius of curvature of the condensate interface is much smaller in the longitudinal direction than in the circumferential direction.
The fin height (h) and the fin‐tip spacing (b) are sufficiently smaller than the fin‐tip radius (Ro).
The radius of curvature at the tube bottom is infinite in the longitudinal direction.
Using the above assumptions, the following expression was produced for retention angle,
where
Honda et al. [12] compared their own experimental data, experimental data of Katz et al. [9] and experimental data of Rudy and Webb [10] using Eq. (3). Good agreement was found between experiment and theory. Later, Rudy and Webb [11] and Owen et al. [13] obtained the same Eq. (3) of condensate‐retention angle for integral‐fin tubes.
Yau et al. [14] reported experimental data for condensate‐retention angle using fluids steam, ethylene glycol and R‐113. Thirteen tubes with rectangular integral fins were tested with a fin height of 1 mm, a thickness of 0.5 mm and a variable‐fin spacing. For tubes with
Liquid retention results with and without drainage strips (after Yau et al. [14]).
Figure 2 also shows a good agreement of experimental data using Eq. (5). A provisional equation for trapezoidal integral‐fin tubes using drainage strips was also suggested as
Masuda and Rose [15] comprehensively analyzed the configuration of the liquid film retained by surface‐tension forces on horizontal low integral‐fin tubes (
Configuration of retained liquid or condensate around a horizontal integral-fin tube. (a) Condensate retention on integral-fin tube. (b) Configuration of liquid around the narrow-spaced integral-fin tube. (c) Configuration of liquid around the wide-spaced integral-fin tube (after Masuda and Rose [15]).
For narrow‐spaced fins (
For narrow‐spaced fins (
For wide‐spaced fins (
For wide‐spaced fins (
Masuda and Rose [15] also defined an ‘active area enhancement ratio’ for low‐rectangular integral‐fin tubes (when
where
and
Rose [16] extended the work and proposed expressions for
and
It was suggested by Masuda and Rose [15] that manufacturing integral‐fin tubes with filleted fin roots would replace the retained wedges of condensate with high‐conductivity metal, and hence increase the active area‐enhancement ratio resulting in more heat transfer. Wen et al. [17] experimentally investigated the effect of fillet fin roots on heat‐transfer enhancement using steam, ethylene glycol and R‐113 as condensing fluids on four integral‐fin tubes. A significant enhancement was found for tubes with filleted roots over tubes without filleted roots.
Briggs [18] obtained static liquid‐retention measurements on 12 three‐dimensional pin‐fin tubes and three integral‐fin tubes. R‐113, ethylene glycol and water were used as test fluids. Static retention measurements were obtained by using two methods: first by taking photographs and second by counting pins. A comparison of both methods of measuring retention angles is shown in Figure 4; it can be seen for water and ethylene glycol, and both methods give results within 15%, but for R‐113, pin‐counting method gives higher‐retention angles compared to the photographic method. Finally, retention angles for water and ethylene glycol were taken as the average of both the methods, but for R‐113, pin‐counting method was used as it was deemed more accurate than photographic method. Liquid retention on three‐dimensional pin‐fin tubes was found to be lower than the equivalent integral‐fin tubes (i.e. with the same longitudinal‐ and radial‐fin dimensions). The controlling parameters appeared to be longitudinal and circumferential pin spacing. A tube with 1‐mm circumferential spacing was found to be optimum for flooding angle. Pin height and longitudinal and circumferential pin thickness had little influence on retention.
Comparison of pin‐counting method with photographic method by Briggs [18].
Comprehensive experimental data for condensate retention (for free convection) were reported on 15 pin‐fin tubes (Figure 5) by Ali and Briggs [19]. Static method to create condensate was adopted to carry out experimentation. Pin‐counting and photographic methods were used to analyse condensate and a comparison of both methods was found to be within ±5%. All pin‐fin tubes were found to be less flooded than the equivalent integral‐fin tubes. A semi‐empirical model was also reported for condensate‐retention angle on pin‐fin tubes as follows:
Sketch of a three‐dimensional pin‐fin tube.
Ali and co‐workers [20–22] have reported in detail studies on condensate retention as a function of vapour velocity on horizontal integral‐fin and pin‐fin tubes. Recently, Ali et al. [23] reported the effect of condensate flow rate on retention angle for horizontal integral‐fin tubes.
Table 1 summarizes the key facts and figures of experimental investigations carried out on enhanced tubes which are described in detail in the following sections.
Investigation | Number of tubes tested | Type of tube | Heat‐transfer coefficient calculation method | Fluids tested | Maximum reported heat‐transfer enhancement ratio |
---|---|---|---|---|---|
Honda et al. [12] | 4 | 3 trapezoidal integral fin 1 saw‐toothed | Direct measurements | R‐113 Methanol | 9.0 6.1 |
Yau et al. [24] | 13 | Rectangular integral fin | Predetermined coolant‐side correlation | Steam | 3.6 |
Masuda and Rose [25] | 14 | Rectangular integral fin | Predetermined coolant‐side correlation | R‐113 | 7.3 |
Masuda and Rose [26] | 14 | Rectangular integral fin | Predetermined coolant‐side correlation | Ethylene glycol | 4.4 |
Wanniarachchi et al. [27, 28] | 24 | Rectangular integral fin | Predetermined coolant‐side correlation | Steam | 5.2 |
Marto et al. [30] | 24 | Rectangular integral fin | Modified Wilson plot | R‐113 | 7.0 |
Sukathme et al. [34] | 12 | 9 trapezoidal integral fins 3 Pin fins | Direct measurements | R‐11 | 10.3 (integral fin) 12.3 (pin fin) |
Briggs et al. [31] | 6 | Rectangular integral fin | Direct measurements | R‐113 ethylene glycol steam | 6.8 4.8 3.0 |
Briggs et al. [35] | 17 (commercial tubes) | 7 two‐dimensional 10 three‐dimensional | Predetermined coolant‐side correlation | R‐113 | 8.2 |
Kumar et al. [37] | 2 | 1 integral fin 1 pin fin | Modified Wilson plot and direct measurements | Steam | 2.5 (integral fin) 3.6 (pin fin) |
Kumar et al. [39] | 8 | 2 integral fins 2 pin fins 4 partial integral fins | Direct measurements | Steam R‐134a | 2.9 6.5 |
Briggs [41] | 6 | Pin‐fin tubes | Predetermined coolant‐side correlation | R‐113 steam | 9.9 2.9 |
Park et al. [33] | 4 | Integral fin | Direct measurements | R‐123 | 5.8 |
Baiser and Briggs [42] | 5 | Pin fin | Predetermined coolant‐side correlation | Steam | 4.1 |
Summary of experimental literature review.
Honda et al. [12] presented heat‐transfer measurements for the condensation of R‐113 and methanol on three integral‐fin tubes and a three‐dimensional saw‐toothed tube. The vapour‐side, heat‐transfer coefficient was found by direct measurements (12–16 thermocouples were placed in each tube wall). The saw‐toothed tube gave the best heat‐transfer enhancements (defined as heat‐transfer coefficient for saw‐toothed tube based on fin‐tip diameter divided by the heat‐transfer coefficient for a smooth tube at the same vapour‐side, temperature difference) for both fluids which was 9.0 and 6.1 for R‐113 and methanol, respectively.
Yau et al. [24] reported an experimental study of dependence of heat transfer on fin spacing for the condensation of steam on horizontal integral‐fin tubes. Thirteen tubes with rectangular fins having a thickness of 0.5 mm and a height of 1.6 mm were tested by systematically varying fin spacing from 0.5 to 20 mm. All tubes were having a fin‐root diameter of 12.7 mm. A plain tube with an outer diameter equal to the fin‐root diameter was also tested for comparison. All tests were performed at near‐atmospheric pressure with vapour flowing vertically downward with velocities between 0.5 and 1.1 m/s. The vapour‐side, heat‐transfer coefficients were found by subtracting the predetermined coolant side and wall resistance from the overall thermal resistance. The observed heat‐transfer enhancement for integral‐fin tubes significantly exceeded the increase in active area. The maximum vapour‐side, heat‐transfer enhancement was found to be around 3.6 for the tube with a fin spacing of 1.5 mm. Integral‐fin tubes with a spacing of 0.5 and 1.0 mm were found to be almost completely flooded by condensate.
Yau et al. [14] also used solid drainage strips with two integral‐fin tubes of fin spacing of 1.5 and 2.0 mm and found that for steam the drainage strip significantly reduced the condensate flooding. The drainage strips were made of copper having a thickness of 0.5 mm and a height of 8 mm. The tubes with strips provided about 25–30% additional heat‐transfer enhancement compared to the same integral‐fin tubes without strips.
Masuda and Rose [25, 26] reported experimental data for the condensation of R‐113 and ethylene glycol on integral‐fin tubes. The effect of fin spacing was investigated on the same set of tubes as used by Yau et al. [14, 24] with the inclusion of a new integral‐fin tube with a fin spacing of 0.25 mm. Predetermined coolant‐side correlation and a modified Wilson plot method were used to evaluate the vapour‐side, heat‐transfer coefficients. For both condensing fluids vapour‐side, heat‐transfer enhancement was found to be about two times higher than the corresponding active area. Tubes with a spacing of 0.5 and 1.0 mm showed best heat‐transfer enhancement of 7.3 for R‐113 and 4.4 for ethylene glycol, respectively.
Masuda and Rose [15] summarized the above experimental investigations by plotting the dependence of vapour‐side, heat‐transfer enhancement against fin spacing. For steam, ethylene glycol and R‐113, tubes with a fin spacing of 1.5, 1 and 0.5 mm, respectively, gave the best heat‐transfer enhancement. They also plotted a graph of active‐area enhancement against fin spacing. For steam, ethylene glycol and R‐113, integral‐fin tubes with a fin spacing of 1.5, 1 and 0.5 mm gave the best active‐area enhancement, respectively. Thus, heat‐transfer enhancement is a maximum for fin spacing that maximize the active area.
Wanniarachchi et al. [27, 28] reported vapour‐side, heat‐transfer measurements for the condensation of steam at atmospheric and low (11.3 kPa) pressure on 24 horizontal rectangular cross‐section integral‐fin tubes made of copper. Fin spacing (0.5, 1.0, 1.5, 2.0, 4.0 mm), fin thickness (0.5, 0.75, 1.0 and 1.5 mm) and fin height (0.5, 1.0, 1.5 and 2.0 mm) were changed systematically to find the best geometry for heat transfer. Vapour‐side, heat‐transfer coefficients were obtained using a predetermined coolant‐side correlation and also by a modified Wilson plot method. Enhancement ratio was found to be strongly dependent on fin spacing and an optimum value was reported between 1.5 and 2.0 mm for all tubes. Fin thickness showed a weak effect on enhancement ratio with an optimum range between 0.75 and 1.0 mm. Enhancement ratio was found to increase with increasing fin height but at a lower rate than the area increase.
Marto et al. [29] presented an experimental study to identify the optimum fin shape to maximize heat transfer. Four integral‐fin tubes with rectangular, triangular, trapezoidal and parabolic fin shapes were tested using steam as the condensing fluid. All tubes had a same fin height and fin‐root spacing and thickness. Tests were carried out at near‐atmospheric and below‐atmospheric pressures. A tube with a roughly parabolic fin shape outperformed the tubes with rectangular, triangular and trapezoidal fin shapes at both pressures.
Marto et al. [30] reported experimental data condensing R‐113 on 24 integral‐fin tubes and a commercially available tube. Fin spacing was varied systematically in a range of 0.25–4 mm for different sets of fin thicknesses. All tests were performed at a little above atmospheric pressure with a downward‐flowing vapour velocity of 0.4 m/s. Vapour‐side, heat‐transfer coefficients were obtained using the modified Wilson plot method with a measured uncertainty in the range of ±7%. The tube with a fin spacing of 0.25 mm and a thickness of 0.5 mm gave the best heat‐transfer enhancement of 7 for a corresponding area enhancement of 3.9. For all tubes tested, heat‐transfer enhancements were found to be considerably higher than the corresponding increase in active areas. The best fin spacing was obtained to be in between 0.2 and 0.5 mm, depending upon the corresponding fin thickness and height. Heat‐transfer coefficient was also found to increase with increase in fin height, but the rate of increase in coefficient of heat transfer was found to decrease with the increase in height.
Briggs et al. [31] reported experimental data for the condensation of steam, ethylene glycol and R‐113 on two sets of integral‐fin tubes. The smaller tubes had a fin‐root diameter of 12.7 mm, fin thickness 0.5 mm and fin height 1.6 mm, whereas the larger tubes had a fin‐root diameter of 19.1 mm and fin thickness and height of 1.0 mm. For both types, three fin spacings of 0.5, 1.0 and 1.5 mm were tested. The outside tube‐wall temperature was measured directly by four embedded thermocouples. For all the smaller tubes, tests were conducted at a little above atmospheric pressure. For larger tubes, tests were performed at a little above atmospheric pressure for steam and R‐113 and also at lower pressures of 3 and 14 kPa for ethylene glycol and steam, respectively. For both larger and smaller diameters, the best‐performing integral‐fin tubes were found with fin spacings of 1.5, 1.0 and 0.5 mm for steam, ethylene glycol and R‐113, respectively. They compared their own experimental data with the indirectly obtained experimental data of earlier investigators [24, 27, 28, 30] and a satisfactory agreement was found.
Briggs et al. [32] reported systematic experimental data for the condensation of steam and R‐113 on rectangular integral‐fin tubes made of copper, brass and bronze, with fin spacing and fin‐root diameter of 1.0 and 12.7 mm, respectively; fin heights and thicknesses varied in the range of 0.5–1.6 mm and 0.25–0.75 mm, respectively. For R‐113, the heat‐transfer enhancement was weakly dependent on fin thermal conductivity but more strongly dependent on fin height and thickness, whereas for steam, the effect of thermal conductivity on heat‐transfer enhancement was much stronger for larger fin heights, but the effect of fin height and thickness was relatively small.
Park et al. [33] obtained experimental data for R‐123 condensing on four integral‐fin tubes used in building chillers with varying fin density in a range of 10 fins per inch to 36 fins per inch. A plain tube with the same outside diameter was also tested to compare the results. The vapour‐side, heat‐transfer coefficients were found directly with embedded thermocouples in the tube wall. The tube with a fin density of 28 fins per inch was found to be optimum with a vapour‐side, heat‐transfer enhancement of 5.8.
Sukathme et al. [34] obtained experimental data for the condensation of R‐11 on nine horizontal integral‐fin tubes and three special pin‐fin tubes made of copper and reported the effect of fin height, fin density and fin‐tip angle on vapour‐side, heat‐transfer coefficients. All tubes were made with trapezoidal fin shapes. Vapour‐side, heat‐transfer coefficients were found from directly measured tube‐wall temperatures, obtained by placing 15 thermocouples at 5 positions along the tube and at top, bottom and mid‐plane around the tube. Fin‐tip angle showed a small effect on the vapour‐side, heat transfer, whereas fin density and fin height showed considerable effects on the vapour‐side, heat‐transfer coefficient. The best‐performing integral‐fin tube with a fin density of 1417 fins per meter, a fin height of 1.22 mm and a fin‐tip angle of 10° gave a vapour‐side, heat‐transfer of 10.3 with a corresponding active‐area enhancement of 7. Further, 80 longitudinal trapezoidal grooves were machined in the best‐performing integral‐fin tube with three different heights of 0.7, 0.9 and 1.22 mm. The authors reported a large increase in vapour‐side, heat‐transfer enhancements with increasing value of height. The pin‐fin tube with a longitudinal groove height of 1.22 mm gave a heat‐transfer enhancement of 12.3 which was about 20% more than the equivalent best‐performing integral‐fin tube. The authors suggested that this increase in heat‐transfer enhancement could be due to the increase in the flooding angle of the pin‐fin tube which was about 20% more than the corresponding integral‐fin tube.
Briggs et al. [35] reported experimental data for the condensation of R‐113 on 17 commercially available copper integral‐fin tubes. These consisted of seven two‐dimensional tubes (Gewa N and K, trapezoidal cross section) and ten three‐dimensional tubes (one thermoexcel and nine petal shaped). It was found that the best two‐dimensional tube (K‐50) and best three‐dimensional tube (P8) gave similar vapour‐side, heat‐transfer enhancement of 8.2.
Cheng et al. [36] obtained condensing data for R‐22 on six commercially available tubes. Two tubes had low integral fin, whereas four were three‐dimensionally enhanced. One set of tubes consisting of an integral‐fin tube, an externally enhanced tube and an externally plus internally enhanced tube has a fin density of 26 fins per inch, fin pitch of 0.97 mm and a height of 1.3 mm, whereas the other set of tubes consisting of one integral‐fin tube, one externally enhanced tube and one externally plus internally enhanced tube has a fin density of 40 fins per inch, fin pitch of 0.61 mm and a fin height of 1.42 mm. Experiments were carried out at three different pressures of 1.3, 1.5 and 1.6 MPa. A Wilson plot method was used to obtain vapour‐side, heat‐transfer coefficients. The three‐dimensional externally plus internally enhanced tubes showed the highest heat‐transfer coefficients compared to rest of the tubes. The heat‐transfer coefficients were found to decrease with increasing value of pressure. It was also found that vapour‐side, heat‐transfer coefficients decreased more sharply for three‐dimensionally enhanced tubes as a function of increasing temperature difference compared to integral‐fin tubes.
Kumar et al. [37] reported experimental data for the condensation of steam on a plain tube with an outside diameter of 22 mm and an integral‐fin tube (with an outside diameter of 25 mm, fin height of 1.1 mm, fin thickness of 1.1 mm and fin spacing of 1.5 mm). A three‐dimensional pin‐fin tube was also tested with similar radial and longitudinal dimensions as of integral‐fin tube but with 40 axial grooves around the circumference producing a circumferential pin spacing of 0.9 mm. The condensing‐side heat‐transfer coefficients were found using a modified Wilson plot method and also by direct measurement of wall temperatures; good agreement was found between the two methods. Vapour‐side, heat‐transfer enhancements of 2.5 and 3.6 were found for the integral‐fin tube and pin‐fin tube, respectively. The superior performance of the pin‐fin tube was thought to be primarily due to the thinning of the condensate film by the surface‐tension pull in two directions in the unflooded area as also proposed by Sukhatme et al. [34] condensing R‐11 and also due to the improved condensate drainage at the bottom of the tube. Authors reported the improved condensate drainage at the bottom part of the pin‐fin tube compared to the condensate drainage for the integral‐fin tube.
Jung et al. [38] reported vapour‐side, heat‐transfer enhancements for an integral‐fin tube with fin density of 26 fins per inch and a three‐dimensional turbo‐C tube with a fin density of 42 fins per inch condensing two low‐pressure (R‐11 and R‐123) and two medium‐pressure (R‐12 and R‐134a) refrigerants. A plain tube was also tested for comparison. Vapour‐side, heat‐transfer coefficients were obtained directly by measuring the tube‐wall temperature with embedded thermocouples. For low‐pressure refrigerants, heat‐transfer coefficients for R‐123 of about 8–19% lower than those of R‐11 were found for all tubes tested. For medium‐pressure refrigerants, heat‐transfer coefficients for R‐134a were about 0–32% higher than those for R‐12. The vapour‐side, heat‐transfer enhancements for turbo‐C and integral‐fin tubes based upon the plain tube area were roughly reported up to 8.0 and 5.5, respectively.
Kumar et al. [39, 40] presented experimental data for the condensation of steam and R‐134a. Five tubes consisting of one plain, one integral‐fin, one pin‐fin and two partial integral‐fin tubes (i.e. one with pin fins on the upper half and one with pin fins on the lower half) were tested for each fluid. For steam, all enhanced tubes had rectangular fins and a fin density of 390 fins per meter, whereas for R‐134a, all enhanced tubes had trapezoidal fins and a fin density of 1560 fins per meter. Pin‐fin tubes were made by machining longitudinal grooves into integral‐fin tubes. Pin‐fin tubes gave the best vapour‐side, heat‐transfer enhancements of 2.9 for steam (30% more than equivalent integral‐fin tube tested) and 6.5 for R‐134a (24% more than equivalent integral‐fin tube tested). Pin fins were reported to be more effective at lower half of the tube than the upper half of the tube, that is, for steam, a heat‐transfer enhancement of 2.4 (with pin fin on the upper half) and 2.7 (with pin fins on the lower half), whereas for R‐134a, a heat‐transfer enhancement of 5.7 (with pin fins on the upper half) and 6.3 (with pin fins on the lower half) was reported. Tubes with pin fins on the lower half outperformed the equivalent integral‐fin tubes by up to 20% for steam and 11% for R‐134a. For R‐134a, pin fins on the upper half of the tube did not contribute in the heat‐transfer enhancement but showed 5% improvement for steam compared to integral‐fin tube.
Briggs [41] reported experimental data for the condensation of R‐113 and steam on six three‐dimensional pin‐fin tubes. These tubes were made by machining rectangular longitudinal grooves into integral‐fin tubes. A plain tube with the same outside diameter as the pin‐fin tube‐root diameter was also tested for comparison purposes. The vapour‐side, heat‐transfer coefficient was obtained by subtracting the coolant and wall resistances from the measured overall resistance. For R‐113, the best‐performing tube had circumferential pin thickness and spacing of 0.5 mm, pin height of 1.6 mm and a longitudinal spacing and thickness of 0.5 mm. For steam, the best‐performing tube had circumferential pin thickness and spacing of 0.5 and 1.0 mm, respectively, and longitudinal thickness of 0.5 mm and spacing of 1.1 mm. Tubes with larger fin heights produced higher heat transfer when all other geometric variables remained the same. For R‐113, the best‐performing tube gave a vapour‐side enhancement of 9.9 compared to the plain tube which was about 40% higher than the equivalent integral‐fin tube with the same fin height, longitudinal thickness and spacing. For steam, the best‐performing tube gave a heat‐transfer enhancement of 2.9 compared to the plain tube which was about 25% higher than the equivalent integral‐fin tube. For R‐113, a near‐linear increase in heat‐transfer enhancement with active‐area enhancement was reported. The heat‐transfer enhancement was approximately twice the active‐area enhancement. For steam, heat‐transfer enhancement was virtually independent of active‐area enhancement. The author also reported that static condensate flooding on pin‐fin tubes was significantly less than the equivalent integral‐fin tubes.
Baiser and Briggs [42] reported experimental data for the condensation of steam at atmospheric pressure and low velocity on five three‐dimensional copper pin‐fin tubes. These were the same tubes used in the investigations of Briggs [18]. All of the tubes had a pin‐fin root diameter of 12.7 mm. Only circumferential thickness and spacing were varied. Vapour‐side, heat‐transfer coefficients were found by subtracting the coolant and wall resistances from the measured overall thermal resistance. All pin‐fin tubes gave higher vapour‐side, heat‐transfer coefficients compared to the equivalent integral‐fin tube. The best heat‐transfer enhancement was found to be 4.1 which was thought to be on par with the best‐reported heat‐transfer enhancement on an optimum integral‐fin tube by Wanniarachchi et al. [28]. It was noted that despite less active area of the pin‐fin tubes compared to the equivalent integral‐fin tube, pin‐fin tubes outperformed the integral‐fin tube. It was suggested due to the fact that in the case of pin‐fin tubes, many small effective surfaces replaced few large surfaces of integral‐fin tubes and these smaller surfaces are far more effective for heat transfer since in gravity‐drained flows, they result in shorter thinner boundary layers, while for surface‐tension‐driven flows, these small surfaces produce many more sharp changes in surface curvature, which result in surface‐tension‐induced pressure gradients which thin the condensate film. An optimum circumferential spacing of 1 mm was also identified which maximized the heat‐transfer rate.
Ali and Briggs [43–46] have reported a comprehensive data for the condensation of R‐113 and ethylene glycol on various pin‐fin tubes. Their work has shown superior heat‐transfer performance of pin‐fin tubes (up to 25%) over the equivalent integral‐fin tubes (i.e. with the same fin height, root diameter and longitudinal pin thickness and spacing).
Another useful method to enhance heat transfer on horizontal tubes is by wrapping the wire on the smooth tube; recently, studies are reported by Ali and Qasim [47, 48].
Beatty and Katz [49] were the first to propose a model for condensation heat transfer on integral‐fin tubes. The model assumed the following points:
Gravity drains the condensate from the vertical fins and from the tube in the inter‐fin spacing.
Surface‐tension effects were entirely ignored, that is, the model did not account for capillary retention on the lower part of the tube or enhanced drainage due to surface tension on the upper part of the tube.
The model ignored condensation on the fin tips.
Condensation on the vertical fin flanks was modelled by applying the Nusselt [3] equation for vertical plates and condensation in the inter‐fin spacing was modelled by applying the Nusselt [3] equation for horizontal tubes. The mean vapour‐side, heat‐transfer coefficient for the integral‐fin tube was calculated as the area‐weighted average of the heat‐transfer coefficient on finned surfaces and on base tube between inter‐fin spacing. The following expression was suggested for the vapour‐side, heat‐transfer coefficient:
where
Rose [16] pointed out that if the condensate drained from the fin flanks to the inter‐fin space and proceeded to drain around the inter‐fin tube surface to the bottom of the tube, then a more appropriate value of the effective fin height would be half of the Beatty and Katz [49] value giving
Briggs and Rose [50] compared the Beatty and Katz [49] model to the results of many of the experimental investigations on integral‐fin tubes discussed above. The model showed acceptable agreement for relatively low surface‐tension fluids but over‐predicted the data for high surface‐tension fluids such as steam and ethylene glycol. The authors explained that this was due to the neglect of surface‐tension effects in the model.
Gregorig [51] discussed the effect of surface tension and pointed out its vital role in enhancing condensation heat transfer. His work addressed a vertical fluted surface; a schematic is shown in Figure 6. The author reported that surface‐tension forces are the dominating factor in determining the heat transfer for fins with a height less than 1.5 mm, as surface‐tension induced pressure gradients due to the variation in the curvature of the vapour‐liquid interface of the condensate on the fin. This induced pressure gradient would drain the condensate in the horizontal direction, over the arc length
Fin parameters of vertical‐fluted tube (after Gregorig [51]).
where S is the distance along the vapour‐liquid interface from the tip of the fin and r is the radius of curvature of the liquid‐vapour interface. Gregorig [51] also gave a relation that described the shape of a convex profile which provides a constant condensate film thickness over the arc length
Adamek [52] defined a family of convex shapes that use surface tension to drain the film. His fin curvature was defined as
where each value of
Kedzierski and Webb [53] validated the Gregorig [51] and Adamek [52] theoretical findings. Using an electrostatic discharge‐machining method with a numerical‐controlled machine head, they produced fin profiles for ζ = 2 and -0.5. R‐11 was used as condensing fluid and experimental data agreed with the predictions to within 5%.
Rudy and Webb [54] presented a model to predict condensation heat‐transfer coefficient including the surface‐tension effects on fin flanks. Heat transfer through the part of the tube below the flooding angle was not considered. They totally ignored body‐forces (gravity) effects on the fin flanks and assumed a constant pressure gradient due to surface tension draining the condensate from the fin flanks into the inter‐fin spacing. They took the radius of the curvature of the condensate surface at the fin tip and fin root as half the fin‐tip thickness and fin‐root spacing, respectively. The result was the following expression for the pressure gradient on the fin flanks:
Using the above expression to replace the body‐force term in the Nusselt expression for the fin flanks, the following result was proposed for vapour‐side, heat‐transfer coefficient:
Honda and Nozu [55] provided a prediction method for heat transfer on horizontal trapezoidal integral‐fin tubes. It was pointed out by the authors that an important factor, which had been ignored in earlier theoretical models, is the non‐uniformity of wall temperature, due to the large difference in heat‐transfer coefficients between the unflooded and flooded regions. Their model incorporated surface tension, gravity and variable wall‐temperature effects. The final expression for average heat‐transfer coefficient is based on two regions: unflooded and flooded. A numerical analysis has been given just for thin film with the help of the following assumptions:
The wall temperature is uniform along the fin.
The condensate flow is laminar.
The condensate film thickness
Circumferential flow on the flanks can be neglected in comparison with radial flow.
Fin height is substantially smaller than the tube outer radius.
The following expression was developed for the condensate film thickness along the fin:
Finally, the following expression was developed for the average Nusselt number for horizontal integral‐fin tubes:
Honda and Nozu [55] compared their theoretical model with their own experimental data for the condensation of R‐113 and methanol on three integral‐fin tubes (see Honda et al. [12]) and found agreement within ±10%. The same experimental data gave agreement with Beatty and Katz [49] model within ±20%. They also compared their theoretical model with the experimental results of previous investigators including for 11 fluids and 22 tubes and found an agreement within ±20%. Briggs and Rose [50] compared the Honda and Nozu [55] model with a range of experimental data of previous investigators and reported that most of the data agreed with the model to within 25%.
Rose [16] pointed out that in most of the proposed heat‐transfer models, either gravity was completely neglected when surface‐tension‐driven drainage was considered on the fin flanks or only the radial component was included. He also suggested the need for a simple heat‐transfer model, in the form of an algebraic expression akin of Beatty and Katz [49], but including surface‐tension effects. Applying dimensional analysis, the following expression for the mean condensate film thickness was proposed that accounts for both gravity and surface‐tension effects:
A and B are constants and found separately for the fin tips, fin flanks and inter‐fin space.
For the fin tip, where there is no retained condensate, the author took the parameters involved in Eq. (27) as
For the unflooded part of the fin flanks, the author took the parameters in Eq. (27) as
where
Finally, for the unflooded part of the tube inter‐fin space, the author took the parameters in Eq. (27) as
From Eqs. (27) and (28) with the appropriate values of A, B,
From Nusselt [3], the expression for the heat flux for a plain tube is
Further, assuming no heat transfer to the flooded and blanked part of fin flanks and inter‐fin space, an enhancement ratio for a pitch length of trapezoidal integral‐fin tube over the plain tube at the same temperature difference was obtained as
Finally, by substituting Eqs. (32)–(35) for the mean heat flux for fin tip, fin flanks and inter‐fin space into Eq. (36), the following final expression is obtained:
In the above expression, to account for the fact that condensate drainage from the fin flanks would affect both gravity and surface‐tension contributions to the heat transfer at the inter‐fin tube space, a lead constant,
Briggs and Rose [1] incorporated ‘fin efficiency’ effects into the model of Rose [16] in an approximate way. This was done by dividing the tube into flooded and unflooded parts. For the flooded part, the fin flanks were assumed adiabatic to find the heat flux through the fin tip,
where
With the help of the above equations, appropriate expressions including temperature variations for flank heat flux,
Finally, the following expression was proposed to calculate vapour‐side, heat‐transfer enhancement ratio:
In the numerator of Eq. (40), the first term shows heat‐transfer rate through the flooded part of the tube, the second term shows heat‐transfer rate through the unflooded part of the fin and the third term shows heat‐transfer rate through the unflooded part of fin spacing. Briggs and Rose [50] compared the experimental data from different investigations to the predictions of the Briggs and Rose [1] model. The inclusion of conduction in the fins on the basis of ‘slender fin theory’ improved the agreement of experimental data for low thermal conductivity tubes (i.e. bronze tubes condensing steam) with the model.
Kumar et al. [40] pointed out that almost all the reported heat‐transfer models refer to condensation on integral‐fin tubes and there was no analytical model for condensation on pin‐fin or spine integral‐fin tubes. They proposed a generalized empirical model to predict the vapour‐side, heat‐transfer coefficient for integral‐fin as well as pin‐fin tubes. They assumed that the heat‐transfer coefficient was a function of fluid properties, tube geometry and condensate mass flow rate. This resulted in an expression for the vapour‐side, heat‐transfer coefficient as follows:
where all the constants in Eq. (41) were found empirically using least‐square method, Re is the condensate film Reynolds number given by
We is the Weber number, the ratio of surface tension and inertia forces in the condensate, and for pin‐fin tubes was estimated as a Pythagorean sum of the Weber numbers for the two perpendicular faces of the pins as follows:
where Wel and Wec are the Webber numbers for the longitudinal and circumferential faces of the pin and are calculated from
Note that for integral‐fin tubes, only longitudinal Weber number is used in Eq. (41).
Y is a function of the tube geometry and is given by
Kumar et al. [40] compared their own experimental data‐condensing steam on two tubes (one integral fin and one pin fin) and R‐134a on five tubes (four integral fins and one pin fin) with the model and reported an agreement within 15% for most of the experimental data. Cavallini et al. [56] compared the model to the experimental data for the condensation of steam and refrigerants on integral‐fin tubes reported by previous researchers and concluded that the model was not appropriate for tubes with heights of more than 1.1 mm and with fin pitches of more than 1.0 mm or less than 0.5 mm for refrigerants and less than 2.0 mm for steam. Namasivayam [57] also compared the model to the experimental data of steam and R‐113 on integral‐fin tubes and agreed with the conclusions of Cavallini et al. [56].
Belghazi et al. [58] presented a model for a specially designed three‐dimensional Gewa C+ tube containing notches around the fin. The tube circumference was divided into flooded and unflooded regions. The authors further divided fin pitch into four regions. It was assumed that for certain regions (i.e. the regions between notches and above notches) surface tension will be the draining force and for other regions (i.e. the region below notches and inter‐fin tube space) gravity will be the draining force. Nusselt [3] theory was applied to find the heat‐transfer coefficients for the gravity‐based drainage regions. By replacing
where
The authors compared their model with their own experimental data, for R‐134a condensing on a Gewa C+ tube. The model predicted most of the experimental data to within
Ali and Briggs [2] developed a simple semi‐empirical correlation accounting for the combined effect of gravity and surface tension for condensation on horizontal pin‐fin tubes. The model divided the heat‐transfer surface into five regions, that is, two types of pin flank, two types of pin root and the pin tip (Figure 7). The following equation was proposed to calculate heat‐transfer enhancement:
In Eq. (47),
Schematic representation of pin‐fin tube identifying five regions for heat transfer (after Ali and Briggs [2]).
The model gave good overall agreement to within ±20% with the experimental data, as well as correctly predicted the dependence of heat‐transfer enhancement on the various geometric parameters and fluid types.
Extensive experimental work has been performed on integral‐fin tubes and has shown that geometry is not the only point of interest for the enhancement of heat transfer. Researchers have reported the optimum fin dimensions for a range of condensing fluids [24–26, 28, 30]. The work of Honda et al. [12] successfully predicts the condensate retention on integral‐fin tubes. Reliable heat‐transfer models (e.g. [1, 55]) accounting for the combined effects of surface tension and gravity on heat transfer have been developed and are readily available for design engineers.
A reasonable amount of experimental work is reported on condensation heat transfer on enhanced pin‐fin tubes. Work of previous researchers has shown the superior performance of such tubes over equivalent integral‐fin tubes. The extent of condensate retention and formation of many sharp surfaces enhancing surface‐tension effects on pin‐fin tubes are identified to be the important parameters contributing towards the heat‐transfer enhancement. The model presented by Ali and Briggs [2] is available to predict heat transfer on the pin‐fin tubes reasonably by accounting the effect of both gravity and surface‐tension condensate drainage.
A constant in Eq. (27)
B constant in Eq. (27)
efin height of convex profile
k thermal conductivity of condensate
L length of flat plate
m
r radius of curvature of the vapour‐liquid interface
S distance along the vapour‐liquid interface measured from the fin tip
Sm total fin arc length
V volume of condensate
x distance along the vapour‐liquid interface measured from the fin tip
Greek Letters
Macrophages represent up to 50% of the cells infiltrating into the tumor microenvironment (TME) and modulation of macrophage polarization is an interesting and novel therapeutic approach in preclinical or clinical cancer research.
An increasing number of studies have also shown that tumor-associated macrophages (TAMs) can antagonize, augment or mediate the antitumor effects of cytotoxic agents, tumor irradiation, anti-angiogenic/vascular damaging agents and checkpoint inhibitors [1].
In the tumor microenvironment, TAMs are one of the major contributors in angiogenesis by secreting pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), adrenomedullin (ADM), platelet-derived growth factor (PDGF), tumor growth factor-beta (TGF-β) and matrix metalloproteinases (MMPs). Also, TAMs promote tumor cell invasion and metastasis by modifying the composition of extracellular matrix and cell-cell junctions and promoting basal membrane disruption. It was demonstrated that macrophages facilitate the metastasis by enhancing the ability of cancer cells to enter a local blood vessel and also are involved in immunosuppression by inhibiting the T-cell response or by secreting immunosuppressive cytokines and proteases such as IL-10, TGF-β, arginase-1 and prostaglandins, which inhibit T-cell activation and proliferation [2].
TAMs often exhibit an array of activation states. In general, they are skewed away from the “classically” activated, tumoricidal phenotype (sometimes referred to as M1) toward an “alternatively” activated tumor-promoting one (M2) [1]. The classically activated M1 macrophages are stimulated by microbial substrates such as lipopolysaccharide, Toll-like receptor ligands and cytokines such as IFN-γ. They are characterized by secretion of pro-inflammatory cytokines such as interleukins IL-6, IL-12, IL-23 and TNF-α and express high levels of major histocompatibility complex class II (MHC-II), CD68, and CD80 and CD86 costimulatory molecules. The alternatively activated M2 macrophages are stimulated by IL-4 and IL-13, secrete IL-10 and TGF-β and express low levels of MHC-II and feature expression of CD163 and CD206 [3].
Unfortunately, M2 cells are the most representative cells of the TAM population within the tumor promoting genetic instability, local immunosuppression and stem cell nurturing [4] and providing essential support for a malignant phenotype [5].
In the early stages of cancers of the lung, colon and stomach, the macrophages in the normoxic milieu display an M1 phenotype and are associated with good prognosis, but within avascular areas of the tumor, TAMs alter the gene expression profile, favoring a protumor M2 phenotype, correlated with a bad prognosis [6]. In Table 1 are showed recent conclusions concerning the correlation between TAMs and clinical prognostics in several tumor types. In human breast carcinomas, high TAM density is also associated with poor prognosis [7]. TAMs in renal cell carcinoma show a mixed M1/M2 phenotype. CD68 alone has a poor predictive value, while low CD11+ and high CD206+ as single variables correlated with reduced survival [8]. There is strong evidence for an inverse relationship between TAM density and clinical prognosis in solid tumors of the breast, prostate, ovary and cervix. Type I and II endometrial carcinomas had significantly higher macrophage density in both epithelial and stromal compartments than benign endometrium [9]. Type II cancers have nearly twice the TAM density of type 1 cancers and this difference may be due to M1 macrophage predominance in the stroma of type II cancers [10].
Cancer type | TAMs as prognostic factors | Reference |
---|---|---|
Breast | CD68 as a biomarker for TAMs to evaluate the risk is better than CD163 or CD206 alone; high infiltration of TAMs was significantly associated with negative hormone receptor status and malignant phenotype | [18] |
Gastric | The amount of TAMs in tumor stroma predicts the size, stage and metastasis of the gastric tumor Invasive front-/stroma-dominant pattern having worse outcomes Although CD68+ TAMs infiltration has the neutral prognostic effects on OS, the M1/M2 polarization of TAMs are predicative factors of prognosis in gastric cancer patients | [11, 12, 19] |
Lung | The prognostic value of tumor-infiltrating TAMs in lung cancer is still controversial. M2 subset and TAMs in tumor stroma were associated with worse survival, while M1 subset and TAMs in tumor islet were associated with favorable survival of lung cancer. CD204-positive TAMs are the preferable marker for prognostic prediction in NSCLC Although the density of total CD68+ TAMs is not associated with overall survival, the localization and M1/M2 polarization of TAMs are potential prognostic predictors of NSCLC | [13, 20, 21] |
Cervix | Tumor-infiltrating CD204+ M2 macrophages may predict poor prognosis in patients with cervical adenocarcinoma | [22] |
Ovarian | CD163+ TAM infiltration was associated with poor prognosis of ovarian cancer and high M1/M2 macrophage ratio in tumor tissues predicted better prognosis | [23] |
Pancreatic | Although TAM populations in tumor stroma are high, marking them as a probable prognostic factor, the multiple roles that TAMs play in pancreatic cancer progression have not yet been delineated. Additional mechanistic insight into the pathways that regulate the differentiation of TAMs from monocytes is required The density of TAMs has an impact on the overall survival of pancreatic cancer patients. M2-TAMs can be recognized as a prognostic indicator in pancreatic cancer | [24, 25] |
Renal | CD68 alone has a poor predictive value, while low CD11+ and high CD206+ as single variables correlated with reduced survival | [8] |
Glioblastoma | TAM, accounting for approximately 30% of the GBM bulk cell population, may explain, at least in part, the immunosuppressive features of GBMs | [26] |
Hepatocellular carcinoma | The prognostic value of TAMs in patients with hepatocellular carcinoma (HCC) is still controversial. TAMs could serve as independent predictive indicators and therapeutic targets for HCC. Further trials are needed to elucidate the exact relationship and the underlying mechanism | [27] |
Melanoma | Independent of their intratumoral distribution, the prevalent accumulation of M2 TAMs in MM is statistically confirmed to be a poor indicator of patients’ outcome | [28] |
Non-Hodgkin’s lymphoma | High-density CD68+ and CD163+ TAMs, and also high CD163+/CD68+ TAMs ratio is significantly correlated with poor overall survival | [29] |
Hodgkin’s lymphoma | High density of either CD68+ or CD163+ TAMs is a robust predictor of adverse outcomes in adult cHL | [30] |
Colorectal (CRC) | The role of tumor-associated macrophages (TAMs) in predicting the prognosis of CRC remains controversial. Still, high-density CD68+ macrophage infiltration can be a good prognostic marker | [31] |
Squamous cell carcinoma of the head and neck (SCCHN) | CD68+ marker has no prognostic utility in patients with SCCHN; the M2-like marker CD163+ predicts poor prognosis | [32] |
TAMs as potential predictive indicators in several tumor types.
TAMs’ distribution pattern could be an independent prognostic factor for the overall survival of gastric cancer patients, invasive front-/stroma-dominant pattern having worse outcomes [11]. Studies have shown that the amount of TAMs in tumor stroma predicts the size, stage and metastasis of the gastric tumor [12]. In lung cancer, M2 subset and TAMs in tumor stroma were associated with worse survival, while M1 subset and TAMs in tumor islet were associated with favorable survival of lung cancer [13].
While most cancer research has focused upon these changes and most therapeutics are directed against these tumor cells, it is now apparent that the non-malignant cells in the microenvironment evolve along with the tumor and provide essential support for their malignant phenotype [5]. The knowledge of TAM activation status may allow the therapeutic targeting of TAMs, once TAMs’ targeting/modulating agents pass clinical trials and become widely available [6, 14]. The role of macrophages in tumor progression remains to be fully elucidated, in part due to the contrasting roles they play depending on their polarization [15]. Both the systemic and local environments play a tumor-initiating role through the generation of persistent inflammatory responses to a variety of stimuli [16]. To support this correlative data between macrophage-mediated inflammation and cancer induction, genetic ablation of the anti-inflammatory transcription factor STAT3 in macrophages results in a chronic inflammatory response in the colon that is sufficient to induce invasive adenocarcinoma. However, it is unclear whether macrophages in some inflammatory situations can kill aberrant cells before they become tumorigenic and thus be antitumoral [17].
Targeting a single signaling axis that promotes the immunosuppressive and protumoral functions of macrophages is inadequate as there are multiple signals involved in the communication between tumor cells and TAMs. Identifying and inhibiting key driver pathways, which are critical for both cancer cell survival and TAM activation, may offer therapeutic advantages as they disrupt the vicious positive feedback loop between tumor and TAMs [33]. Prevention of TAM accumulation and reduction of TAM presence by depleting existing TAMs represent novel strategies for an indirect cancer therapy specifically aimed at tumor-promoting cells within the microenvironment, but the challenge with this approach is to find ways for local administration of such drugs to the tumor [15]. Targeting TAM polarity toward an M1 phenotype also became a real immunotherapeutical approach in cancer, recalling responses from both innate and adaptive immune systems, leading to tumor regression [4].
Triple combination of anti-CTLA-4, anti-PD-1 and G47Δ-mIL12 was associated with macrophage influx and M1-like polarization in two glioma models [34]. A combination of a bivalent ganglioside and β-glucan, a yeast-derived polysaccharide, able to differentiate TAMs into an M1 phenotype is currently under investigation in a phase I clinical trial of patients with neuroblastoma [35]. Vadimezan, a fused tricyclic analog of flavone acetic acid, was found to repolarize macrophages in M1 phenotype, and it has been the subject of numerous preclinical studies and clinical trials [36]. Zoledronic acid, a clinical drug for cancer therapy, has been found to inhibit spontaneous mammary carcinogenesis by reverting macrophages from the M2 phenotype to the M1 phenotype [37].
Research to date suggests that, despite the potency of cytotoxic anticancer agents and the high specificity that can be achieved by immunotherapy, neither of these two types of treatment is sufficient to eradicate the disease. Moreover, even in standard chemotherapy, there has been efficiency through the introduction into current practice of treatments with combinations of drugs [38]. In general, literature data show that the combination of conventional treatment with natural compounds exerts an additive effect caused by the alternative activation of signaling pathways that induce cell death or increase the activity of the chemotherapeutic agent. The involvement of these natural compounds (alone or in combination therapy) in the immunobiology of cancer is a branch that has not yet been studied but offers major therapeutic opportunities. Herbal compounds have many regulatory effects on macrophage polarization, but the specific mechanisms, signaling pathways and target genes involved remain incompletely understood [39]. Their effects, according to recent research studies, are summarized in Figure 1.
Herbal compounds and their main actions on TAMs in cancer progression.
Although natural products have historically been a critical source for therapeutic drugs, sometimes natural molecules may suffer from insufficient efficacy, unacceptable pharmacokinetic properties, undesirable toxicity or reduced availability, which impedes their direct therapeutic application. Poor availability of some natural compounds, despite their pharmacological effects, limits their clinical application. In recent years, there has been an increased interest in developing nanoformulations with increased bioavailability and fewer side effects. For instance, TAM-rich tumors, due to their enhanced permeability, demonstrated an elevated retention (>700%) of the nanotherapeutic (poly(
Triterpenic compounds, including corosolic acid, tigogenin, timosaponin AIII, neoaspidistrin and oleanolic acid, suppress the CD163 expression. Corosolic and oleanolic acids change M2 polarization to M1 polarization in human monocyte-derived macrophages (HMDMs) by suppressing STAT3 and NF-kB activation. The effects of these two compounds were exerted not only on macrophages but also on glioblastoma cells, suppressing tumor cell proliferation and sensitizing tumor cells to anticancer drugs [40, 41].
M2 polarization was switched also by astragaloside IV (AS-IV, 3-O-β-
A potential role of celastrol, a pentacyclic triterpenoid in antimetastasis treatment, was suggested by Yang et al. [45], which found that this compound suppresses M2-like polarization by interfering with STAT6 signaling pathway after stimulation with IL-13. An active role in decreasing macrophage recruitment and tumor angiogenesis was showed for lupeol and stigmasterol in an in vivo model [46].
Treatment with 9-hydroxycanthin-6-one, a β-carboline alkaloid isolated from the Ailanthus altissima stem bark, inhibited the levels of M2 phenotype markers and some cancer-promoting factors, such as MMP-2, MMP-9 and VEGF, in macrophages educated in ovarian cancer–conditioned medium. The compound also decreased the expressions of MCP-1 and RANTES, major determinants of macrophage recruitment at tumor sites, in ovarian cancer cells [47].
A regulatory effect on macrophage differentiation during tumor development exerts phlenumdines E, A, hupermine A and 12-epi-lycopodine-N-oxide isolated from the club moss Phlegmariurus nummulariifolius (Blume) Ching, which exhibited an inhibitory effect on IL-10–induced expression of CD163, an M2 phenotype marker, in HMDMs [48].
Sophoridine, a bioactive alkaloid extracted from the seeds of Sophora alopecuroides L, was able to reshape gastric cancer immune microenvironment by shifting TAM polarization to M1 and suppressing M2-TAM polarization through TLR4/IRF3 axis [49].
In a model of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis, it was showed that isoliquiritigenin (6′-deoxychalcone) inhibits M2 macrophage polarization depending on the downregulation of the IL-6/STAT3 pathway [50]. The same mechanism was proposed by Sumiyoshi et al. [51], for xanthoangelol and 4-hydroxyderricin, chalcones isolated from Angelica keiskei roots. In the in vivo study, the antitumor action of xanthoangelol was higher than that of 4-hydroxyderricin and it was proposed that the presence of a 4-free phenolic OH and/or the presence of a longer isoprene moiety in C-3 could be the cause of better activity of xanthoangelol. Reducing breast cancer cells’ migration with the aid of M2 macrophages was achieved in vitro by the total flavonoid from Glycyrrhizae Radix et Rhizoma and isoliquiritigenin. These compounds inhibited gene and protein expression of Arg-1, upregulated gene of HO-1 and protein expression of iNOS, and enhanced the expression of microRNA 155 and its target gene SHIP1 [52].
Macrophage infiltration and differentiation of macrophages into tumor-promoting M2 macrophage were decreased by epigallocatechin gallate (EGCG) treatment in murine tumor models and the molecular mechanism proposed was the downregulation of NF-κB pathway [53, 54]. EGCG can be rapidly degraded in vivo limiting its clinical application. A peracetate-protected EGCG (Pro-EGCG) synthesized by modification of the reactive hydroxyl groups with peracetate groups proved six times more stability than EGCG and showed greater efficacy in induction of cell death in leukemic cells. Treatment with Pro-EGCG inhibits differentiation of macrophages toward TAMs through decreasing CXCL12 expression in endometrial stromal cells with no influence on the expression level of CD163 and CD206 [55].
Luteolin, 3 0,4 0,5,7-tetrahydroxyflavone, is a common flavonoid derived from various plants and inhibits IL-4–induced phosphorylation of STAT6 and the TAM phenotype, ameliorating the recruitment of monocytes and the migration of lung cancer cells by the reduction of chemokine CCL2 secretion from macrophages [56]. The antitumor mechanism of luteolin in non-small cell lung carcinoma (NSCLC) was mediated by downregulation of TAM receptor tyrosine kinases (RTKs), and it was found to decrease the protein levels of all three TAM RTKs in the A549 and A549/CisR cells in a dose-dependent manner [57]. In an in vitro tumor model, cobalt chloride (CoCl2) was used to simulate hypoxia and it was showed that luteolin decreased the expression of VEGF and MMP-9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF-1 and phosphorylated-signal transducer and activator of STAT3 signaling, particularly within the M2-like TAMs [58].
The regulation of M2 macrophage repolarization through inhibiting PI3K/Akt signal pathway is the mechanism proposed for baicalein (5,6,7-trihydroxyflavone), a widely used Chinese herbal medicine derived from the root of Scutellaria baicalensis. Changing the phenotype of macrophages from M2 to M1 was supported by decreasing of M2-specific marker CD206 correlated to the increased M1-specific marker CD86. Still, the authors of the study suggested that the cytotoxic effect of baicalein on breast cancer cells directly is more pronounced than on TAMs (IC 50 of baicalein for MDA-MB-231 at 24 h, 48 h and 72 h was 79.12/50.10/34.77 μmol/L, for MCF-7 at 24 h, 48 h and 72 h was 49.76/43.73/39.44 μmol/L, for TAM at 24 h, 48 h and 72 h was 191.5/107.1/41.78 μmol/L, respectively) [59].
It has been reported that a novel chrysin (5,7-dihydroxyflavone) analog 8-bromo-7-methoxychrysin has anticancer activities with more potent bioactivity than the lead compound [60]. It also has the capacity to regulate the tumor microenvironment by inhibition of NF-κB activation, suppressing significantly the expression of the M2 macrophage marker CD163 and modulating the secretion profile of TAM cytokines [61].
According to traditional Chinese medicine (TCM) theory, herbs with Qi-tonifying character are involved in improving the defense capacity of immune system. Total flavonoids from Glycyrrhizae Radix et Rhizoma significantly inhibited the expression of Arg-1 (above 90% at 100 μg/mL), one of the phenotype markers of M2 macrophages, and suppressed M2 polarization of macrophages partly by inactivating STAT6 pathway. The regulation of M1 and M2 markers’ expressions was partly due to the enhancement of miR-155 levels [62].
Naringin (4′,5,7 trihydroxyflavanone-7-rhamnoglucoside) exert a potential inhibitory effect on tumor progression by inducing CD169-positive and M1-like macrophages, potentially correlating with cytotoxic T-cell activation [63].
Puerarin [4H-1-benzopyran-4-one, 8-β-
Another isoflavone, genistein, can inhibit the increased M2 polarization of macrophages and stemness of ovarian cancer cells by co-culture of macrophages with ovarian cancer stem-like cells through disrupting IL-8/STAT3 signaling axis [65].
Chlorogenic acid (5-caffeoylquinic acid, CA), the ester of caffeic acid, is a phenolic compound widely found in plants. It was showed that this compound inhibits growth of G422 glioma in vivo, an effect associated with a decrease of M2-like TAMs and recruitment of M1-like TAMs into tumor tissue. Low dose (1 μM) of CA could significantly inhibit the M2 macrophage-induced proliferation of glioma and breast cancer cells, mainly via STAT1 and STAT6 signaling pathways [66]. Oršolić et al. [67] concluded that the antitumor activity of CA is the result of the synergistic activities of different mechanisms by which CA acts on proliferation, angiogenesis, immunomodulation and survival. Mice with Ehrlich ascites tumor (EAT) and treated for 10 days with CA in a dose of 40 and/or 80 mg kg−1 showed an increase of the cytotoxic actions of M1 macrophages and inhibition of the tumor growth, probably mediated through its antioxidative activity.
Deoxyschizandrin, a major dibenzocyclooctadiene lignan present in Schisandra chinensis berries, significantly suppressed CD163 and CD209 expression, inhibiting protumor mediator production as well as M2 polarization in TAM macrophages stimulated by the conditioned medium of A2780 cells [68].
Several studies focused on a stilbene derivative, resveratrol (3,4′,5-trihydroxystilbene), a widely studied compound that exhibits potent preventive effects on lifestyle-related disorders such as hyperlipidemia, obesity, coronary heart disease and cancer, as well as on aging. In lung cancer tumors, resveratrol induced their sluggish growth by decreasing F4/80 positive expressing cells and M2 polarization (lower expression of M2 markers‑IL-10, Arg-1 and CD206), probably by STAT3 suppression [69]. Antitumor and antimetastatic effects of resveratrol (25 and 50 μM) based on the regulation of M2 macrophage activation and differentiation were confirmed by Kimura and Sumiyoshi [70], which also conducted a study for correlation of stilbene structure with biological activity. Among the nine stilbenes examined, 2,3-,3,4-, and 4,4′-dihydroxystilbene inhibited the production of MCP-1 in M2-polarized THP-1 macrophages at a concentration of 50 μM, demonstrating that the inhibitory effects of stilbenes with dihydroxy groups on the production of MCP-1 were greater than those with mono-hydroxyl groups. Dihydroxystilbene at 25 and 50 μM, 3,4-dihydroxystilbene at 50 μM, and 4,4′-dihydroxystilbene at 10, 25 and 50 μM significantly inhibited the production of IL-10 by M2 THP-1 macrophages. The three dihydroxystilbenes, 2,3-, 3,4-, and 4,4′-dihydroxystilbenes, at concentrations of 10–50 μM inhibited p-STAT3 increase during M2 THP-1 macrophage differentiation induced by IL-4 plus IL-13 [71].
The resveratrol analogue, HS-1793 (4-(6-hydroxy-2-naphthyl)-1,3-benzenediol), was also shown to elevate the level of IFN-γ production conducting reprograming of TAMs M2 phenotype [72].
Curcumin ((1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione), a natural phenol and the main active ingredient in turmeric, acts in several ways as a suppressor of macrophage functions. Even though curcumin has previously received considerable attention from researchers as an anti-inflammatory agent, it has a promising future in the area of immunomodulation [73]. Most of the studies on curcumin focused on the anti-inflammatory effect, promoting the conversion of macrophages from M1 to an anti-inflammatory and protective M2 phenotype [73]. Gao et al. [74] demonstrated that curcumin plays a key role in M2 polarization in two ways: (1) via the inhibition of DNA methyltransferase3b (DNMT3b), overexpression of which can promote increased M1 polarization, and (2) via increased phosphorylation of signal transducer and activator of transcription STAT-6, an important transcription factor activated by IL-4 and IL-10. Other studies showed that curcumin also induces TAMs re-polarization from tumor-promoting M2 phenotype toward the more antitumor M1 phenotype in tumor-bearing hosts, mediated by inhibition of STAT3 activity [75]. Curcumin administration and delivery to glioblastoma brain tumors (GBM) caused a dramatic re-polarization of TAMs from an M2 to M1 phenotype and tumor remission in 50–60% of GBM-bearing mice [76]. Hydrazinocurcumin, a synthetic analog of curcumin encapsulated within nanoparticles, reeducates TAMs to an M1-like phenotype IL-10 low IL-12 high TGF-β low [54].
It was showed that TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate (molar ratio C:E:R: 4:1:12.5) can shift TAM polarity in HPV-positive HNSCC by silencing the M2 TAM and activating/recruiting a discrete population of M1 TAM while maintaining a constant number of overall intra-tumor Iba1+ TAM, along with expression of activated STAT3 and induction of activated STAT1 and NF-kB (p65) [77]. Moreover, a liposomal formulation of TriCurin with increased bioavailability (TrLp) was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells [78].
In a urethane-induced lung carcinogenic model, lung carcinogenesis was ameliorated with increased M1 macrophages and decreased M2 macrophages in the lung interstitial by administration of 6-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone), the main bioactive component in ginger (Zingiber officinale Roscoe). M2 macrophage-resetting efficacy of 6-gingerol was confirmed in a Lewis lung cancer allograft model and the mechanism proposed was the reduction of Arg-1 and ROS levels and elevation of L-arginine and NO levels [79].
Also, it was showed that paeoniflorin, one of the major active constituents of Paeonia lactiflora Pallas, inhibits the alternative activation of macrophages in subcutaneous xenograft tumors of the C57BL/6 J mice at doses of 40 and 20 mg·kg−1 [80].
It was suggested that modulation of TAM polarization was implicated in the antitumor immunostimulatory activity of polysaccharides from Panax japonicus (ginseng). The transcription and production of TGF-β and IL-10, two well-known immunosuppressive cytokines secreted by TAMs, were reduced in response to Panax polysaccharides and also the number of infiltrated CD168+ M2 TAMs was substantially declined although the number of CD68+ total macrophages in transplanted tumor tissues remained almost unchanged [81]. A significant inhibition of Arg-1 expression (above 90% at 100 μg/mL), one of the phenotype markers of M2 macrophages, was also observed for the ethanol extract of Ginseng Radix et Rhizoma [62]. Recently, Chen et al. [82], showed that water extract of Ginseng and Astragalus could be a novel option for integrative cancer therapies due mainly to their ability to regulate macrophage polarization.
In a murine model of sarcoma, immunotherapy with IAPS-2 (acidic polysaccharide, namely IAPS-2, from the root of Ilex asprella) demonstrated that it could significantly inhibit the growth of tumors via modulating the function of TAMs and increase the animal survival rate [83]. Similar results were obtained with an aqueous extract of Trametes robiniophila Murr (Huaier), a sandy beige mushroom found on the truck of trees and has been widely used in TCM for approximately 1600 years for its antitumor, antiangiogenic and immunomodulatory effects. Huaier not only modulates the macrophage polarization but also could inhibit the macrophage-induced angiogenesis by decreasing the expression of VEGF, MMP2 and MMP9, thus inhibiting the formation of new blood vessels in tumor [84].
Esculetin (6,7-dihydroxycoumarin) and fraxetin (6-methoxy-7,8-dihydroxycoumarin) (50, 75 and 100 μM) inhibited the production of IL-10, MCP-1 and TGF-β-1 in macrophages and the phosphorylation of STAT 3 without affecting its expression during the differentiation of M2 macrophages. Esculetin also suppressed the increased production of these cytokines during M2 macrophage differentiation at 10–100 μM. On the other hand, daphentin (7,8-dihydroxycoumarin) had no such effects, revealing that coumarins with two hydroxyl groups at the 6 and 7 positions (esculetin) or coumarins with a methoxy group at the 6 and two hydroxyl groups at the 7 and 8 positions (fraxetin) are more active, exhibiting antitumor and antimetastatic actions in osteosarcoma LM8 cells [85]. The antitumor and antimetastatic actions of esculetin may be due to the dual actions at tumor and TAM sites: inhibition of the expression of cyclin D 1 and CDK4 in osteosarcoma LM8 cells, and also decreasing the STAT 3 phosphorylation in macrophages. In the case of fraxetin, the effects are partly attributed to the inhibition of M2 macrophage differentiation [85].
A classical formula of traditional Chinese medicine (TCM) to alleviate lung cancer–related symptoms is Bu-Fei decoction (BFD), consisting of six herbal Chinese medicines‑Codonopsis pilosula, Schisandra chinensis, Rehmannia glutinosa, Astragalus sp., Aster sp. and Morus sp.‑but it has not been established whether it induces an antitumor effect or it modulates the tumor microenvironment. The result of an in vivo study revealed that BFD successfully interrupted the interaction between tumor cells and TAMs by inhibiting the expression of two important markers: IL-10 (correlated with late stage (stage II, III and IV), lymph node metastases, pleural invasion, lymphovascular invasion and poor differentiation in NSCLC patients) and PD-L1 (correlated with poor prognosis in a number of human cancers, including breast cancer, kidney cancer and NSCLCs) [86].
It has been shown that emodin (6-methyl-1,3,8-trihydroxyanthraquinone), the active ingredient of several Chinese herbs including Rhubarb (Rheum palmatum), inhibits the growth of a variety of tumors and enhances the responsiveness of tumors to chemotherapy agents. In breast cancer, emodin directly inhibited macrophage infiltration and M2 polarization in the tumors, independent of tumor size [87]. Previously, Jia et al. [88], showed that emodin is not cytotoxic to breast cancer cells at concentration achieved in vivo (up to 30 μM) and it failed to affect macrophage infiltration in primary tumors. In contrast to its lack of effects on primary tumors, emodin dramatically suppressed lung metastasis by diminishing phosphorylation of STAT6 and C/EBPβ signaling upon IL-4 stimulation [88]. Further, it was showed that emodin suppresses the activation of multiple signaling pathways, including NF-kB, IRF5, MAPK, STAT1 or STAT6, and IRF4, depending on the environmental settings. It acts mostly on M2 polarization, suggesting that emodin could be most beneficial for patients with M2 macrophage-driven diseases [89].
In oral squamous cell carcinoma (OSCC) animal models, highly pure super critical CO2 leaf extract of Azadirachta indica (Neem) induces an M1 phenotype in TAMs in vivo, and the primary active component, nimbolide (a limonoid tetranortriterpenoid with an α,β-unsaturated ketone system and a δ-lactone ring) has significant anticancer activity in established OSCC xenografts [90]. β-Elemene, a widely known sesquiterpene, regulated the polarization of macrophages from M2 to M1, inhibiting the proliferation, migration and invasion of lung cancer cells and enhancing its radiosensitivity [91].
Onionin A (ONA), a natural low molecular weight compound containing sulfur isolated from onions, inhibited the EOC cell-induced M2 polarization of HMDMs, and STAT3 activation was significantly inhibited by ONA treatment in all cell lines [92].
Adjunctive treatment with Withaferin A, the most abundant constituent of Withania somnifera (Ashwagandha) root extract, reduced myeloid cell-mediated immune suppression and polarized immunity toward a tumor-rejecting type 1 phenotype, facilitating the development of antitumor immunity [93].
Traditional Chinese medicine provides pharmacologically efficient preparates such as KSG-002, a hydroalcoholic extract of radices Astragalus membranaceus and Angelica gigas at 3: 1 ratio that suppresses breast cancer growth and metastasis through targeting NF-κB–mediated TNF α production in macrophages [94] and SH003, mixed extract from Astragalus membranaceus, Angelica gigas and Trichosanthes kirilowii Maximowicz that suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path [95].
Traditional Chinese medicine Jianpi Yangzheng Decoction (JPYZ) used for improving the quality of life and prolonging the survival of gastric cancer patients was more effective compared with Jianpi Yangzheng Xiaozheng Decoction (JPYZXZ) for inducing the phenotypic change in macrophages from M2 to M1. JPYZXZ inhibits the gastric cancer EMT more effectively than JPYZ, but JPYZ primarily works to regulate the phenotypic change in macrophages from M2 to M1 [96].
CXCL-1 was also found to be a cytokine secreted by tumor-associated macrophage, which recruits myeloid-derived suppressor cells to form pre-metastatic niche and led to liver metastasis from colorectal cancer. The current study demonstrated that after administration of XIAOPI formula (consisting of 10 herbs including Epimedium brevicornum, Cistanche deserticola, Leonurus heterophyllus, Salvia miltiorrhiza, Curcuma aromatica, Rhizoma Curcumae, Ligustrum lucidum, Radix Polygoni Multiflori preparata, Crassostrea gigas and Carapax trionycis), the density of TAMs decreased significantly and the level of CXCL-1 was also inhibited in both mouse plasma and cellular supernatants. When CXCL-1 cytokine was co-administrated with XIAOPI formula, the antimetastatic property of XIAOPI formula was blocked, indicating that CXCL-1 might be the principal gene involved in the network regulating the action of XIAOPI formula [97].
Macrophages, as key players in the tumor microenvironment, play essential roles in maintenance and progression of malignant state. Due to their plasticity, these cells balance between pro- and antitumoral effects in close correlation to specific factors. Recent immunotherapeutic strategies focus on tumor-associated macrophages in two main directions: to inhibit protumor macrophages and their suppressive effects (CCL2 inhibitors, trabectedin, zoledronic acid, JAK/STAT inhibitors, etc.) and to activate TAMs to an antitumor phenotype (TLR and CD40 agonists, PI3kδ inhibitor, VEGF and Ang2 inhibitors, etc.).
Several natural compounds/herbal extracts were studied as therapeutic/supportive agents for macrophage modulation in different types of cancers, most of them being able to change M2 polarization (protumoral) to M1 polarization (antitumoral). They belong to various classes of herbal compounds: saponins (corosolic and oleanolic acids, astragaloside, ginsenosides, celastrol, etc.), alkaloids (9-hydroxycanthin-6-one, phlenumdines E, A, hupermine A and 12-epi-lycopodine-N-oxide, sophoridine, etc.), flavonoids and polyphenolcarboxylic acids (isoliquiritigenin, xanthoangelol and 4-hydroxyderricin, baicalein, naringin, genistein, deoxyschizandrin, chlorogenic acid, curcumin, 6-gingerol and paeoniflorin), polysaccharides (isolated from various vegetal sources), coumarins (esculetin, fraxetin, etc.), and anthraquinones (emodin). This action is most probably achieved by downregulation of the STAT3, STAT 6 and NF-kB pathways with consecutive modulation of the secretory profile of TAM cytokines.
TCM supports the dual approach of cancer therapy, to destroy cancer cells on one hand and to improve patients’ immunological status on the other hand. For several preparations such as Jianpi Yangzheng Decoction, Bu-Fei decoction and XIAOPI formula, research studies proved the correlation between cancer cells and tumor microenvironment and the effective intervention of these herbal products in delaying/breaking the tumorigenic process.
Low solubility of some herbal compounds limits their clinical application and it conducted to designing of new analogs with improved bioavailability‑ginseng-derived nanoparticles, peracetate-protected EGCG, chrysin and resveratrol analogs.
By now, many herbal compounds have been shown to exhibit antitumor effects in various cancer types. Further, more researches need to be focused on the influence of these valuable compounds/preparations on modulation of the tumor microenvironment, as key element in the relation of tumor-host.
This research was financially supported by the Ministry of Research and Innovation in the frame of the project PN.16.41.01.01/2018, CORE Program.
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