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",isbn:"978-1-83969-221-5",printIsbn:"978-1-83969-220-8",pdfIsbn:"978-1-83969-222-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"ec438b5e4be44dc63870c1ace6a56ed2",bookSignature:"Dr. Marcos Roberto Tovani Palone",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10710.jpg",keywords:"Orofacial Cleft, Cleft Lip, Surgery, Cleft Palate, Oral Surgical Procedures, Orthodontics, Dental Treatment, Comprehensive Dental Care, Speech Therapy, Speech-Language Pathology, Pediatric Treatment, Therapy",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 3rd 2021",dateEndSecondStepPublish:"March 3rd 2021",dateEndThirdStepPublish:"May 2nd 2021",dateEndFourthStepPublish:"July 21st 2021",dateEndFifthStepPublish:"September 19th 2021",remainingDaysToSecondStep:"2 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Marcos Roberto Tovani Palone received his Ph.D. from Ribeirão Preto Medical School, University of São Paulo, Brazil. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"46827",title:"Recovery from ICH – Potential Targets",doi:"10.5772/58477",slug:"recovery-from-ich-potential-targets",body:'Intracerebral hemorrhage (ICH) is a devastating clinical event caused by rupture of blood vessels and accumulation of blood in the brain. Many disorders, including hypertensive arteriosclerosis, amyloid angiopathy, neoplasia, coagulation disorders and cerebrovascular malformations, directly or indirectly damage blood vessels in the brain and thus lead to ICH. The annual occurrence of ICH is estimated to be approximately 0.12 million in the USA and 2 million in the world. These numbers are expected to increase due to the aging of populations. Although accounting for only 15-20% of all strokes, ICH has severe clinical symptoms and poor prognosis. The 1-year survival rate of ICH is estimated to be 38% and long-term physical and mental disability is found in more than 90% of the survivors. Sadly, there is no effective treatment for ICH. Currently, primary supportive care and risk factor control are the main therapy for ICH in clinics. Thus, research and development of effective reagents to treat ICH is extremely urgent. In this chapter, we first introduce the anatomy and biology of the blood brain barrier. Then the pathophysiology and animal models of ICH are reviewed. Furthermore, we summarize the potential therapeutic targets for ICH.
One unique feature about the blood vessels in the brain is the presence of the blood-brain barrier (BBB). BBB is a natural barrier that separates the central nervous system (CNS) from the circulation [1]. Under physiological conditions, the BBB prevents the entrance of blood cells and large molecules into the brain, but allows the uptake of nutrients and hormones from the blood, maintaining the homeostasis of CNS microenvironment [1, 2]. Under pathological conditions, the integrity of BBB is compromised and blood components leak into the brain, contributing to the progress of diseases [3-12]. At the cellular level, the BBB consists of brain microvascular endothelial cells (BMECs), astrocytes, pericytes, neurons, microglia, and the non-cellular component-basement membrane [13] (Figure 1).
Schematic illustration of BBB. The BBB is composed of cellular and non-cellular components. Cellular components include BMECs, perycites, astrocytic endfeet, neurons, and microglia. Non-cellular components includes the basement membrane.
BMECs
Endothelial cells in the CNS, BMECs, are different in many ways from the ones in the periphery. First, BMECs have more mitochondria, lower pinocytotic activity, and little-to-no fenestrations. Second, the endothelium in the brain and the spinal cord is 50-100 times tighter than that in the rest of the body [14]. In the CNS, BMECs connect to each other via tight junctions, which are unique structures that confer impermeability to the BBB. Two types of proteins are found at tight junctions: transmembrane proteins, including occludin and claudins, and cytoplasmic accessory proteins, including zonula occluden-1, 2, 3 (ZO-1, 2, 3) and cingulin [15, 16]. The transmembrane proteins seal gaps between adjacent cells, decreasing intercellular permeability [17, 18], whereas cytoplasmic accessory proteins link transmembrane proteins to cortical actin-based cytoskeleton, enabling strict regulation of the distribution of tight junction proteins (TJP) [19, 20].
Besides intercellular transportation, intracellular transportation is another way to regulate BBB permeability [11, 21-23]. Although small lipophilic molecules, such as oxygen and carbon dioxide, can diffuse across BMECs freely [24], the transport of large hydrophilic molecules is mediated by specific transporters or receptors. Based on their subcellular distribution and functions, these transporters and receptors are divided into three groups. Group I transporters are expressed on both luminal and abluminal sides of BMECs and function to transport nutrients between the blood and brain [25, 26]. For example, glucose transporter 1 (GLUT1) transports glucose; monocarboxylate transporter 1 (MCT1) transports lactate; the L1 and y+transporters transport large neutral and cationic essential amino acids to and from the brain. Group II transporters are also expressed on both sides of BMECs, but only transport materials in one direction [27-29]. For example, transferrin and insulin receptors (TFR and IR) are expressed on both sides of BMECs. The luminal and abluminal receptors mediate endocytosis of transferrin and insulin from the blood and brain, respectively. Group III transporters are expressed on only one side of BMECs and usually mediate one-way transportation of materials [26, 30-38]. For instance, in order to remove excitatory neurotransmitter glutamate from the brain, excitatory amino acid transporters (EAATs) are exclusively expressed on the abluminal side of BMECs. Similarly, to facilitate the removal of amyloid-β from the brain, low-density lipoprotein receptor related protein 1 (LRP1) is solely expressed on the abluminal side of BMECs. Another example of such transporters is (Na+-K+) ATPase, which is only found on the abluminal side to regulate ion homeostasis and thus proper neuronal & synaptic functions. Additionally, multidrug resistance related protein 1 (MRP1) and P-glycoprotein (P-gp) are primarily expressed on BMEC luminal side to efflux many types of drugs from the brain. The subcellular distribution of these transporters and receptors is summarized in Figure 2.
Major transporters and receptors expressed by BMECs. Three groups of transporters are expressed in BMECs. Group I includes GLUT1, MCT1, L1 and y+transporters, which are expressed on both luminal and abluminal sides of BMECs and transport materials bi-directionally. Group II includes TRP and IR, which are expressed on both sides of BMRCs but transport materials in one direction. Group III includes EAATs, LRP1, (Na+-K+)ATPase, MRP1 and P-gp, wich are expressed on only one side of BMECs.
Astrocytes
More than 30 years ago Stewart and Wiley, using xenograft experiments, demonstrated that the unique properties of BMECs, including increased mitochondria number, few pinocytotic vesicles and presence of tight junctions [39], were induced by the microenvironment of the CNS. Astrocytes, which constitute the major glial cells in the brain that cover more than 99% of the vascular surface using their extended endfeet [40, 41], have been suggested to contribute to these unique features of BMECs as well as the impermeability of BBB. Consistent with this hypothesis, temporary focal loss of astrocytes positively correlates with the compromise of BBB integrity in vivo [42]. Additionally, injected astrocytes have been shown to cover the blood vessels in the eye and prevent the leakage of Evans blue from the circulation system [43]. Moreover, in vitro culture experiments revealed that BMEC-astrocyte co-culture had a higher transendothelial electrical resistance (TEER) and less leakage of tracers, compared to BMEC monolayer [44-46]. Further mechanistic studies have demonstrated that both direct contact and astrocyte-secreted soluble factors, such as Ang1, TGF-β, GDNF and FGF2, are responsible for the impermeability of BBB [47-49]. These data suggest that astrocytes, by interacting with BMECs directly and indirectly, contribute to the unique properties of BMECs and the impermeability of BBB. Therefore, the co-culture of BMEC with astrocytes has been one of the most widely used in vitro BBB models, since it replicates in a petri dish the tight structures observed in vivo.
Pericytes
Discovered in 1873, pericytes are perivascular cells sandwiched between endothelial cells and astrocytic endfeet [50]. They are embedded in the basement membrane under normal conditions [1]. Pericytes cover capillaries and the degree of coverage varies depending on the species and tissue type[51]. It has been shown that the pericyte-to-endothelial ratio is 1:5 in rats, 1:4 in mice, and 1:3-4 in humans [52, 53]. In mice, this ratio is 1:1 in retina, 1:3 in brain and 1:100 in skeletal muscle vasculature [54], representing how tightly the blood vessels and their contents are confined in different tissues. Pericytes have several different developmental origins, depending on the organs they cover [51]. In the brain and thymus, pericytes arise from ectoderm-derived neural crest, whereas they differentiate from the mesothelium in the lungs, liver, and gut [51]. So far, there are no pericyte-specific markers available [51], although many cellular markers, including α-smooth muscle actin (SMA), PDGFRβ, Desmin, CD13, NG2, and RGS-5, have been used to identify pericytes, primarily in combination, as none of these markers is exclusive for these cells (pericytes share markers with myofibroblasts, vascular smooth muscle cells and neuronal progenitors [51]). It should be noted that the expression of these markers is high dependent on the differentiation stage of pericytes.
The main functions of pericytes include BBB regulation, vascular development and injury repair [52, 55, 56]. Here we focus on BBB regulation. It has been shown that pericyte-deficient mice have compromised BBB and pericyte coverage positively correlates with the tightness of tight junction [11, 57, 58]. Additionally, pericytes migrate away from capillaries, decreasing their coverage, under pathological conditions, such as hypoxia and traumatic brain injury [59, 60]. These data suggest that pericytes play a critical role in BBB integrity and maintenance. Mechanistic studies demonstrate that BBB breakdown in pericyte-deficient mice is due to diminished expression of BBB-specific genes in endothelial cells and lack of polarity in astrocytic endfeet [58]. Consistent with these data, adding pericytes to BMEC-astrocyte co-culture system significantly enhanced TEER and decreased the leakage of tracers [61, 62]. Further studies showed that the function of pericytes on BBB integrity is also dependent on the differentiation stage of pericytes [63]. TGF-β treated pericytes, which are further differentiated SMA+pericytes, compromise BBB integrity. On the contrary, b-FGF treated pericytes, which are less differentiated SMA-pericytes, maintain impermeability of BBB. Altogether, these data suggest that pericytes is a key regulator of the BBB integrity. Nowadays, BMEC-pericyte-astrocyte triple-culture is becoming more and more popular in BBB research.
Neurons
In the human brain, the number of neurons and capillaries is estimated to be the same [64]. Both BMECs and astrocytic processes are directly innervated by noradrenergic, serotonergic, cholinergic, and GABA-ergic neurons [65-71]. The fact that local neuronal activity and metabolism regulate cerebral blood flow (neurovascular coupling) suggests that neurons may regulate BBB permeability through modulating BMEC and astrocyte function [72]. Consistent with these data, adding neurons to in vitro BBB models significantly increases the tightness of the BBB [73]. However, the exact mechanism underlying how neurons contribute to the BBB integrity is still elusive. Many studies focus on such mechanisms.
Microglia
Microglia, the brain resident immune competent cells, account for 10-20% of glial cells in the brain [74, 75]. Fate mapping studies suggest that they originate from Myb-independent, FLT3-independent, but PU.1-dependent myeloid progenitors that express colony stimulating factor 1 receptor (Csf1R) at embryonic day 8.5 [76-80]. Under physiological conditions, microglia have a ramified morphology, characterized by a small cell body and many long/thin dynamic processes [75]. By extending and retracting these dynamic processes, microglia survey the changes of microenvironment in the brain [75]. Once an insult is identified, microglia quickly undergo a process collectively termed activation, which involves changes to ameboid morphology. Activated microglia migrate to the site of injury, proliferate locally, secrete pro-and anti-inflammatory cytokines, and remove cellular debris by phagocytosis [74, 81-83]. Microglia play a dual role in the brain. On one hand, they contribute to neurite growth and neuronal survival by clearing cell debris and releasing neurotrophic factors [84-86], such as neurotrophin-3 and brain-derived neurotrophic factor. On the other hand, microglia secrete high levels of pro-inflammatory cytokines, including TNF-α and IL-1β, promoting neuronal death. The former (neuroprotective microglia) display anti-inflammatory properties and are called M2 cells, similar to the nomenclature of macrophages. The latter, secreting pro-inflammatory cytokines, exhibit neurotoxic behaviors and are called M1 microglia. Which role they play is highly dependent on the timing after injury and the type of injury. Since microglia are close to other components of the BBB in the brain, they may regulate BBB integrity either by directly interacting with the blood vessels, or indirectly through interaction with BMECs, astrocyte endfeet, or pericytes [87]. Interestingly, microglial activation has been reported to both compromise and restore BBB integrity [88, 89]. This discrepancy could be explained by different injury models and different timing after injury. More work is needed to answer the question how microglia regulate BBB integrity.
Basement Membrane (BM)
BM is a 3-dimensional network composed of extracellular matrix (ECM) proteins, including collagens, laminins, heparin sulfate proteoglycans, and nidogens [47, 90]. The formation of this network involves polymerization and cross-link of these ECM proteins [90, 91]. At the BBB, BMECs generate a vascular BM and astrocytes generate a parenchymal BM [92, 93]. The vascular and parenchymal BM is usually indistinguishable at capillaries [1]. However, at the post-capillary venules, the two BMs are separated by perivascular space where cerebrospinal fluid drains, and where antigen-presenting cells can be found [1]. Both BM layers have the same composition except that in the vascular BM laminin-α4 and-α5 are predominantly present [93], whereas in the parenchymal BM laminins-α1 and-α2 are the main components [92-94].
Accumulating evidence suggests that loss of BM results in disruption of BBB, probably due to the loss of a physical barrier at the BMEC-astrocyte interface and/or lack of signaling from ECM molecules [95-99]. Individual ECM proteins, including laminin, collagen type IV, and fibronectin, have been shown to increase the TEER of BMECs in vitro [100]. Using laminin conditional knockout mice, we have shown that astrocytic laminin maintains BBB integrity by preventing pericyte differentiation from the resting stage to the contractile stage [101]. In addition, laminin α5 and dystroglycan, a major receptor for ECM proteins, have been found to negatively correlate with the infiltration of leukocytes in the brain [93]. These data suggest that BM plays a crucial role in BBB regulation. Future studies are expected to focus on the roles of individual ECM proteins in BBB integrity. Understanding how these ECM proteins affect individual BBB components and BBB integrity would significantly enhance our knowledge on BBB and potentially pave the way for the treatment of many neurological disorders.
When ICH occurs, blood leaks into the brain parenchyma, leading to the formation of hematoma, which quickly increases intracranial pressure. The accumulated blood and high intracranial pressure cause immediate primary damage to the brain. This initial injury is followed by secondary damage mainly resulting from inflammatory responses [102, 103]. The exposure of brain parenchyma to blood proteins (e.g., proteases and hemoglobin) and cells (red blood cells and leukocytes) results in activation of microglia, and the secretion of pro-inflammatory cytokines/chemokines [104, 105], including TNF-α, IL-1β, and MCP1/CCL2. These inflammatory mediators, by forming a concentration gradient, activate and attract more microglia and other inflammatory cells to the injury site [106]. These cells then accumulate around the hematoma, forming a barrier to prevent the spread of injury to other sites. The released pro-inflammatory cytokines/chemokines and possibly activated microglia also act on BMECs, pericytes and astrocytes, leading to compromise of BBB integrity. Through the disrupted BBB, peripheral leukocytes infiltrate into the brain. The infiltrated leukocytes together with activated microglia produce more pro-inflammatory mediators, which induce cell death in the penumbra area [107, 108]. In addition, hemolysis of red blood cells causes iron deposition in the brain parenchyma and subsequent lipid peroxidation [109]. Free radicals generated during lipid peroxidation also lead to cell death and contribute to ICH-induced brain injury [110, 111]. With the progress of disease, microglia and infiltrated leukocytes change their gene expression profile from pro-inflammatory to anti-inflammatory and clear up the dead cells via phagocytosis [110, 112]. The clearance of cell debris finally leads to the resolution of the hematoma and repair of damaged tissue. At this stage, the activated inflammatory cells revert to a resting state again. Due to the limited regenerative ability of neurons, however, most neurological functions cannot be recovered, which explains the high extent of disability after ICH.
To study ICH and eventually cure this disease, several ICH animal models have been developed, including collagenase ICH model, whole blood ICH model, and the spontaneous ICH model. Although these models have been widely used in ICH research, none of them fully replicates the pathology of ICH in human patients. Here we briefly discuss the advantages and disadvantages of these models.
Collagenase ICH Model
This model utilizes the enzymatic activity of collagenase, a bacterial enzyme. After injection into the brain, collagenase induces rupture of blood vessels by degrading collagen IV, a component of the blood vessel wall [103-105]. The rupture of blood vessels then induces the formation of hematoma and other pathological alterations. There are many advantages of this model. First, ICH induced by collagenase injection is very reliable and reproducible. The size and location of hematoma reported by different laboratories across the world are comparable [112-115]. Second, the location of hematoma can be controlled depending on the site of injection. Third, this model is very simple and fast. ICH can be induced within hours after collagenase injection. Due to these advantages, collagenase ICH model has become one of the most popular animal models for ICH research. This model, however, also has a few disadvantages. One of the most significant drawbacks is that it introduces collagenase, a bacterial enzyme, into the mammalian brain. This enzyme degrades ECM proteins in the brain, affects BBB integrity, and modifies inflammatory or immune responses, all of which may affect ICH progress [105, 116, 117]. Another disadvantage of this model is that it does not replicate the vascular challenges usually seen before the onset of ICH in patients, such as hypertension and atherosclerosis. Mice lacking these vascular injuries may have different disease progress and/or recovery patterns, which makes it difficult to interpret data generated using this ICH model.
Whole Blood ICH Model
The whole blood model involves injection of blood from the same animal or a donor into the brain. The injected blood induces secondary pathological changes observed in human patients. Unlike the collagenase ICH model, this model does not introduce exogenous enzymes. The application of this ICH model, however, is circumvented by its three major disadvantages. First, the whole blood ICH model lacks pathological changes in blood vessels. The vascular challenges and rupture of vasculature cannot be replicated in this model. Second, this model is less reproducible than collagenase ICH model. The size and location of hematoma vary depending on different laboratories. Third, the shape of hematoma is different from that found in human patients. Hematoma formed in whole blood ICH model is usually umbrella-shaped and narrower slit-like [118]. This unique shape is probably caused by high pressure-induced rapid distribution of blood along white matter tracts and/or corpus callosum after injection. A way to get around this problem is used in bigger animals, like pigs, where a space/balloon forming initial injection is followed by the injection of the homologous whole blood.
Spontaneous ICH Model
To better replicate the pathological changes observed in human patients, a spontaneous ICH model has been developed in rodents [119]. This new model induces ICH through acute hypertension, the most common etiology of hemorrhage in humans. In this model, animals are administered with NG-nitro-L-arginine methyl ester (L-NAME) and angiotensin II to induce hypertension. The injection of angiotensin II causes surges of blood pressure, which eventually lead to rupture of blood vessels and thus ICH. This spontaneous ICH model replicates most pathological alterations observed in human patients. However, the time it takes to induce ICH is relatively long (2-4 weeks), the location of the ICH varies, and the reproducibility still needs further investigation.
ICH is a devastating clinical event. Sadly, no effective treatments are available at present. Current therapy is mainly supportive care [120, 121]. Due to the pivotal role of inflammatory responses in ICH development, anti-inflammatory strategies have been explored by many laboratories. Here we review a few anti-inflammatory targets with therapeutic potential in ICH: microglial activation, leukocyte infiltration, cytokines/chemokines, protease activation, and reactive oxygen species (ROS) production. In addition, stem cell therapy is also discussed briefly.
Microglial Activation
Microglia are one of the first cell types that respond to ICH. In collagenase ICH model, microglial activation starts at 1 hour [102, 122], peaks at 3-7 days [104, 105, 115, 123], and returns to a resting state again by 3-4 weeks after the onset of ICH [124, 125]. A similar time course of microglial activation is observed in whole blood ICH model [122, 124, 125]. Since activated microglia contribute to the amplification of inflammatory responses and cell death by secreting chemotactic cytokines and cytotoxic mediators, including proteases and ROS [102, 103, 112, 115], inhibition of microglial activation has been proposed as a therapeutic strategy for ICH. It has been shown that pre-or post-treatment with the tri-peptide microglia/macrophage inhibitory factor (MIF, Thr-Lys-Pro) significantly inhibited microglial activation, reduced injury size and improved neurological function [104, 105]. Consistently with this report, inhibiting microglial activation with neuroprotectant minocycline in both collagenase and whole blood ICH models protected BBB integrity, decreased brain edema, and improved functional recovery, although neuronal death remained changed [126-130]. These data support that inhibition of microglial activation is beneficial. However, there is also evidence suggesting that long-term inhibition of microglial activation is detrimental [104, 115]. Given that activated microglia also contribute to the clearance of cell debris and recovery at late stage, inhibition of microglial activation should be limited to the early stage. The question then becomes how to define early and late stages after ICH? Definition of these stages would significantly improve the outcome of ICH treatments.
Leukocyte Infiltration
Leukocytes infiltrate into the brain through the compromised BBB and modulate the progress and/or recovery of ICH [102, 112]. Among all the subtypes of leukocytes, neutrophils are the earliest ones to infiltrate into the brain after ICH. In both collagenase and whole blood ICH models in rodents, neutrophil infiltration starts at approximately 4 hours and peaks at 3 days after the onset of ICH [102, 115, 124, 131, 132]. These cells promote cell death and brain damage by producing ROS and pro-inflammatory mediators [107, 108], and usually die within 2 days in the brain. Mice deficient for CD18, a subunit of β2 integrin indispensable for leukocyte infiltration, demonstrated reduced brain edema and mortality as well as decreased leukocyte number in the brain after collagenase injection [133]. In human postmortem brains, leukocyte infiltration was also observed within hours after ICH [134, 135]. Furthermore, leukocyte counts in blood have been found to positively correlate with injury size in ICH patients [136]. Therefore, high leukocyte counts together with other factors have been used to predict early clinical outcome in ICH patients [137, 138]. Currently, no anti-leukocyte infiltration strategies have been investigated in ICH models. Obtaining such data may facilitate the research and development of novel reagents targeting leukocyte infiltration.
Cytokines/Chemokines
During ICH, activated microglia and infiltrated leukocytes produce high levels of inflammatory cytokines/chemokines, which mediate the secondary damage to the brain. In both rodents and humans, pro-inflammatory cytokines, including TNF-α and IL-1β, are transiently up-regulated in the peri-hematomal region [106, 139]. In addition, chemokines and chemokine receptors that mediate leukocyte extravasation, including CCL2-4, IL-8, CXCL5, and CCR1-2, are also increased/activated [139, 140]. These data suggest that targeting cytokine/chemokine signaling may be a therapeutic strategy for ICH. In collagenase ICH model, we have found that mice deficient for CCL2 or its receptor CCR2 have a mild but delayed disease progression [115]. In CCL2-/-or CCR2-/-mice, hematoma was smaller at day 1 post injury (dpi 1) but larger at subsequent times (dpi 7 and 14 [115]), indicating a delayed recovery. Consistent with the crucial role of CCL2-CCR2 system in microglial activation/migration, limited numbers of microglia were observed at dpi 1 in both knockout mice [115]. At dpi 3 and 7, however, the number of microglia in the knockout mice far exceeded those in control animals [115], suggesting that CCL2-CCR2 independent alternative signaling recruited microglia in the knockout mice. The infiltration of neutrophils was also ablated in both knockout mice at dpi 1 and 3, echoed by the smaller hematoma size early after injury [115]. In addition, at dpi 7 the expression of inducible nitric oxide synthase (iNOS) decreased in controls compared to earlier time-points, but remained high in the mutant mice, indicating that lack of CCL2-CCR2 signaling produces more ROS. Moreover, brain edema, neuronal loss and neurological function followed similar trends over time as that of hematoma size [115]. Altogether, these data suggest that inhibiting CCL2-CCR2 signaling early after ICH is neuroprotective, whereas long-term inhibition delays the recovery. Future work should focus on developing the best CCL2-CCR2 inhibition regimen for ICH patients.
Protease Activation
ICH activates many proteases, including matrix metalloproteinases (MMPs). MMPs are a group of zinc-dependent proteases actively involved in extracellular remodeling and neuroinflammation. Under physiological conditions, low levels of inactive MMPs are found in the brain. These MMPs, however, are dramatically up-regulated and activated when ICH occurs [112, 141]. We and others have demonstrated that collagenase quickly activates and up-regulates the expression of MMP-2,-3,-9, and-12 in rodents [112, 142]. Activation of MMP-9 has also been described in other ICH models [143-145]. In human ICH patients, blood MMP-9 level has been reported to correlate with BBB integrity, hematoma size, edema of the penumbra area, and neurological function [138, 146, 147], whereas blood MMP-3 levels have been found to associate with mortality [148]. Additionally, higher level of MMP-9 was detected in the peri-hematomal region in postmortem human brains [113, 149]. These data suggest that modulation of MMP activity may have therapeutic effect in ICH. Consistent with this hypothesis, mice lacking MMP-3,-9, or-12 are partially protected from ICH [141, 144, 150]. In addition, the therapeutic effect of MMP inhibitors has also been investigated. GM6001, a broad-spectrum MMP inhibitor, has been found to be neuroprotective in both collagenase and whole blood ICH models in mice [132, 151]. Similar results have been noted for BB-1101, another broad-spectrum MMP inhibitor [152]. However, both neuroprotective and detrimental roles have been reported for MMP inhibitor BB-94, depending on the animal models used [153-155]. Besides its inhibitory effect on microglial activation, minocycline also functions as a MMP inhibitor [126]. There is evidence suggesting that minocycline reduces TNF-α level and brain edema without affecting neuronal loss [127, 156], when administered 6 hours after ICH. Together, these data suggest that MMPs, especially MMP-9, play a detrimental role in ICH, and that MMP inhibitors may be used, alone or in combination with other medicine, to treat ICH.
ROS Production
One of the main pathological changes of ICH is the accumulation of blood in the brain. The hemolysis of extravasated red blood cells leads to degradation of hemoglobin and deposition of iron in the brain [109]. In rats, a 3-fold increase of non-heme iron was found after ICH [109]. Accumulated iron has been shown to induce oxidative stress by formation of free radicals, mediate secondary inflammatory injury, and contribute to brain atrophy and neurological deficits after ICH [157, 158]. In human patients with spontaneous ICH, blood ferritin level associates with brain edema in peri-hematomal region [159]. In addition, iron level in the hematoma also correlates with brain edema in peri-hematomal area [160]. These data suggest that iron deposition contributes to brain damage, and that removing the deposited iron may be an appropriate therapeutic approach. Consistent with this hypothesis, 2, 2\'-dipyridyl, a lipid-soluble iron chelator, has been shown to be beneficial in both the collagenase and whole blood ICH models in mice [161]. Another iron chelator deferoxamine has shown neuroprotective effects in the whole blood ICH model in rats and piglets [162-165]. In collagenase ICH model, however, deferoxamine failed to show any beneficial effects [166], suggesting the effect of deferoxamine depends on ICH animal models. None-the-less high doses of deferoxamine are currently examined in clinical trials (starting in 2012) for the treatment of ICH.
An alternative way to treat iron-induced oxidative stress is to target antioxidant enzymes. To remove extra ROS, antioxidant enzymes, including glutathione S transferases, glutathione peroxidase, and glutamate-cysteine ligase, are up-regulated. The key transcription factor that controls the expression of these antioxidant enzymes is Nrf2 [167]. Nrf2 is expressed in neuronal and glial cells in the brain. Activation of Nrf2 has been shown to be neuroprotective both in vitro and in vivo [168, 169]. Additionally, mice deficient for Nrf2 showed more severe neurological deficits compared to wild-type mice in both collagenase and whole blood ICH models [170, 171]. Paralleled with neurological deficits, enhanced ROS production and leukocyte infiltration were observed in Nrf2-/-mice [170, 171]. More importantly, sulforaphane, an Nrf2 inducer, has been reported to improve neurological deficits in mice when administered 30 minutes after ICH [170]. Together, these data suggest that Nrf2 is a target with therapeutic potential.
Stem Cell Therapy
ICH induces neuronal death and loss of neurological function. Multipotent stem cells with the ability to differentiate into neurons are a potential therapy for ICH. It has been reported that human neural stem cells are able to differentiate into neurons and astrocytes, and thus improve neurological function after intravenous injection in collagenase ICH model [172]. Stem cell therapy is relatively new and more work is needed before it can be used in ICH patients. For example, the route, dose and timing of stem cell injection need to be optimized; the differentiation, proliferation and integration of stem cells in vivo should be investigated; and the side effects of stem cell administration must be examined.
Accumulating evidence suggests that the secondary inflammatory responses play a critical role in the development of ICH, indicating that the molecular mechanism of inflammation is an ideal target for the therapy of ICH. As discussed, many pathways, including microglia activation, leukocyte infiltration, cytokine/chemokine secretion, protease activation, and ROS production, have been explored, and several compounds showed significant potential in the treatment of ICH. However, it should be noted that the animal models used in the studies are not perfect, which limits the interpretation of experimental data. Thus, other models and human samples should be used to confirm the results before they are used in patients.
Breast cancer is the most frequently diagnosed cancer among women worldwide, affecting over 1.5 million women each year. In 2015, it is estimated that worldwide 500,000 women have died from this malignancy, which represents 15% of all cancer-related deaths among women [1].
\nIt is now well recognized that breast cancer comprises a heterogeneous group of diseases in term of differentiation and proliferation, prognosis and treatment. Over the past decades, microarray-based gene expression studies have allowed the identification of breast cancer intrinsic subtypes [2, 3, 4]. One of these subtypes is the so-called human epidermal growth factor receptor 2 (HER2)-enriched subtype. HER2 is a transmembrane tyrosine kinase receptor [5]. This protein is encoded by the HER2 gene, which is located on the long arm of chromosome 17 (17q12–21.32) [6]. The HER2-enriched subtype is characterized by high expression of HER2 and other genes of the 17q amplicon, including growth factor receptor bound protein 7 (GRB7), and low to intermediate expression of luminal genes such as Estrogen Receptor 1 (ESR1) and Progesterone Receptor (PGR) [7]. Clinically, HER2-positive breast cancer occurs in 15–20% of breast cancer patients and is characterized by the overexpression of the HER2 receptor and/or HER2 gene amplification [8]. HER2-positive breast cancer patients have a particular worse prognosis. Importantly, HER2-positive breast cancer patients are eligible to receive targeted treatment with trastuzumab, a monoclonal antibody specifically directed against the HER2 receptor [9]. Trastuzumab treatment, in combination with chemotherapy, improves the outcome of early [10, 11] and metastatic [12, 13] HER2-positive breast cancer patients. The US Food and Drug Administration (FDA) approved trastuzumab for the treatment of metastatic HER2-positive breast cancer patients in 1998 and for the treatment of early HER2-positive breast cancer patients in 2006. Lapatinib is a small-molecule inhibitor of the intracellular tyrosine kinase domain of both HER2 and EGFR receptors [14]. Lapatinib has received FDA approval in 2007 as combination therapy with capecitabine for the treatment of patients with HER2-positive advanced breast cancer patients who had progressed on trastuzumab-based regimens [15]. Although anti-HER2 agents are generally well tolerated, trastuzumab administration has been associated with cardiac side effects, especially when used in combination with anthracyclines [16].
\nHER2 plays a significant role in breast cancer pathogenesis. It is therefore essential to understand the biology of this receptor in order to better treat HER2-positive breast cancer patients. Evaluation of HER2 status in breast cancer specimens raises several technical considerations. In the last decades, several methods have been developed for HER2 assessment. In this article, we will review important aspects of the HER2 biology and its relevance in breast cancer and present the techniques that are used in clinical practice for the determination of HER2 status in breast cancer specimens.
\nThe HER2 receptor is a 185 kDa transmembrane protein that is encoded by the HER2 (also known as erb-b2 receptor tyrosine kinase 2 [ERBB2]) gene, which is located on the long arm of chromosome 17 (17q12–21.32) [6]. HER2 is normally expressed on cell membranes of epithelial cells of several organs like the breast and the skin, as well as gastrointestinal, respiratory, reproductive, and urinary tract [17]. In normal breast epithelial cells, HER2 is expressed at low levels (two copies of the HER2 gene and up to 20,000 HER2 receptors) [18], whereas in HER2-positive breast cancer cells, there is an increase in the number of HER2 gene copies (up to 25–50, termed gene amplification) and HER2 receptors (up to 40 to 100 fold increase, termed protein overexpression), resulting in up to 2 million receptors expressed at the tumor cell surface [19]. Besides breast cancer, HER2 overexpression has also been reported in other types of tumors, including stomach, ovary, colon, bladder, lung, uterine cervix, head and neck, and esophageal cancer as well as uterine serous endometrial carcinoma [20].
\nHER2 belongs to the epidermal growth factor receptor (EGFR) family. This family is composed of four HER receptors: human epidermal growth factor receptor 1 (HER1) (also termed EGFR), HER2, human epidermal growth factor receptor 3 (HER3), and human epidermal growth factor receptor 4 (HER4) [5].
\nHER family members are transmembrane receptor tyrosine kinases. Tyrosine kinases are enzymes that carry out tyrosine phosphorylation, namely the transfer of the γ phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrate [21].
\nHER receptors share a similar structure. They are composed of an extracellular domain (ECD), a transmembrane segment and an intracellular region [22]. The ECD domain is divided into four parts: domains I and III, which play a role in ligand binding, and domains II and IV, which contain several cysteine residues that are important for disulfide bond formation [23]. The transmembrane segment is composed of 19–25 amino acid residues. The intracellular region is composed of a juxtamembrane segment, a functional protein kinase domain (with the exception of HER3 that lacks tyrosine kinase activity [24] and must partner with another family member to be activated [25]), and a C-terminal tail containing multiple phosphorylation sites required for propagation of downstream signaling [23]. The catalytic domain contains the ATP binding pocket, a conserved site essential to ATP binding [26].
\nHER receptors are activated by both homo- and heterodimerization, generally induced by ligand binding [27]. This suggests that HER receptor family has evolved to provide a high degree of signal diversity [28]. The cellular outcome produced by HER receptors activation depends on the signaling pathways that are induced, as well as their magnitude and duration, which are influenced by the composition of the dimer and the identity of the ligand [28].
\nSeveral growth factor ligands interact with the HER receptors [29]. HER1 receptor is activated by six ligands: epidermal growth factor (EGF), epigen (EPG), transforming growth factor α (TGFα), amphiregulin, heparin-binding EGF-like growth factor, betacellulin and epiregulin. HER3 and HER4 receptors bind neuregulins (neuregulin-1, neuregulin-2, neuregulin-3, and neuregulin-4). HER2 is a co-receptor for many ligands and is often transactivated by EGF-like ligands, inducing the formation of HER1-HER2 heterodimers. Neuregulins induces the formation of HER2-HER3 and HER2-HER4 heterodimers [29]. However, no known ligand can promote HER2 homodimer formation, implying that no ligand can bind directly to HER2 [30].
\nThe structural basis for receptor dimerization has been elucidated in recent years through crystallographic studies [31, 32]. Dimerization is mediated by the dimerization arm, a region of the extracellular region of HER receptors. While in its inactivated state the dimerization arm of EGFR, HER3 and HER4 is hidden, ligand binding induces a receptor conformational change leading to exposure of the dimerization arm [31]. In contrast to the other three HER receptors, the dimerization arm of the HER2 receptor is permanently partially exposed, thus permitting its dimerization even if the HER2 receptor lacks ligand-binding activity [32].
\nInteraction between the dimerization arms of two HER receptors promotes the formation of a stable receptor dimer in which the kinase regions of both receptors are closed enough to permit transphosphorylation of tyrosine residues, i.e. the transfer of a phosphate group by a protein kinase to a tyrosine residue in a different kinase molecule [33, 34]. The first member of the dimer mediates the phosphorylation of the second, and the second dimer mediates the phosphorylation of the first [23].
\nThe phosphorylation of specific tyrosine residues following HER receptor activation and the subsequent recruitment and activation of downstream signaling proteins leads to activation of downstream signaling pathways promoting cell proliferation, survival, migration, adhesion, angiogenesis and differentiation [35]. The Phosphatidylinositol 3′-kinase (PI3K)-Akt pathway and the Ras/Raf/MEK/ERK pathway (also known as extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway) are the two most important and most extensively studied downstream signaling pathways that are activated by the HER receptors [5, 36]. These downstream signaling cascades control cell cycle, cell growth and survival, apoptosis, metabolism and angiogenesis [37, 38]. Signaling from HER receptors is then terminated through the internalization of the activated receptors from the cell surface by endocytosis. Internalized receptors are then either recycled back to the plasma membrane (HER2, HER3, HER4) or degraded in lysosomes (HER1) [39, 40].
\nHER heterodimers produce more potent signal transduction than homodimers. This can be explained by the fact that heterodimerization provides additional phosphotyrosine residues necessary for the recruitment of effector proteins [28]. Heterodimerization follows a strict hierarchical principle with HER2 representing the preferred dimerization and signaling partner for all other members of the HER family [41]. HER2 seems to function mainly as a co-receptor, increasing the affinity of ligand binding to dimerized receptor complexes [42, 43]. HER2 has the strongest catalytic kinase activity [41] and HER2-containing heterodimers produce intracellular signals that are significantly stronger than signals generated from other HER heterodimers [44]. The HER2-HER3 heterodimer in particular exhibits extremely potent mitogenic activity through the stimulation of the PI3K/Akt pathway, a master regulator of cell growth and survival [45]. Furthermore, HER2 containing heterodimers have a slow rate of receptor internalization, which results in prolonged stimulation of downstream signaling pathways [28]. HER2 can also be activated by complexing with other membrane receptors, such as Insulin-like growth factor I receptor (IGF-1R) [46].
\nWhereas in normal cells the activity of tyrosine kinases is a tightly controlled mechanism, in cancer cells, alterations in tyrosine kinases—overexpression of receptor tyrosine kinase proteins, amplification or mutation in the corresponding gene, abnormal stimulation by autocrine growth factors loop or delayed degradation of activated receptor tyrosine kinase—lead to constitutive kinase activation and therefore to aberrant cellular growth and proliferation [34, 47]. Constitutive activation of HER1, HER2, HER3, IGF-1R, Fibroblast growth factor receptor (FGFR), c-Met, Insulin Receptor (IR), Vascular Endothelial Growth Factor Receptor (VEGFR), Jak kinases and Src have been associated with human cancer [34, 48, 49, 50, 51, 52].
\nSeveral ways of aberrant activation of HER receptors have been described, including ligand binding, molecular structural alterations, lack of the phosphatase activity, or overexpression of the HER receptor [53].
\nIn HER2-positive tumors, receptor overexpression has been identified as the mechanism of HER2 activation. The increased amount of cell surface HER2 receptors associated with HER2 overexpression leads to increased receptor-receptor interactions, provoking a sustained tyrosine phosphorylation of the kinase domain and therefore constant activation of the signaling pathways. HER2 overexpression also enhances HER2 heterodimerization with HER1 and HER3 [54] resulting in an increased activation of the downstream signaling pathways. It has also been shown that HER2 overexpression leads to enhanced HER1 membrane expression and HER1 signaling activity through interference with the endocytic regulation of HER1 [54, 55, 56]. While HER1 undergoes endocytic degradation after ligand-mediated activation and homodimerization, HER1-HER2 heterodimers evade endocytic degradation in favor of the recycling pathway [57, 58], resulting in increased HER1 membrane expression and activity [55, 56, 59].
\nIt has also been reported that HER2 overexpression enhances cell proliferation through the rapid degradation of the cyclin-dependent kinase (Cdk) inhibitor p27 and the upregulation of factors that promote cell cycle progression, including Cdk6 and cyclins D1 and E [60].
\nSeveral methods have been developed for the assessment of HER2 status in breast cancer specimens, at the protein level, DNA level, and RNA level. Here below, we present some of the existing techniques that are used for the HER2 determination in clinical practice.
\nIHC allows the evaluation of the HER2 protein expression in formalin-fixed, paraffin-embedded (FFPE) tissues using specific antibodies directed against the HER2 receptor protein [61]. HER2 receptor is then visualized with the chromogen 3,3′-diaminobenzidine tetrahydrochloride (DAB) resulting in a brownish membranous staining. Several commercially available diagnostic tests for the determination of HER2 expression have been approved by the FDA: the HercepTest™ kit (DAKO, Glostrup, Denmark), the InSite™ HER2/neu kit (clone CB11; BioGenex Laboratories, San Ramon, CA), the Pathway™ kit (clone 4B5; Ventana Medical Systems, Tucson, AZ), and the Bond Oracle HER2 IHC System (Leica Biosystems, Newcastle, UK).
\nBy this method, it is possible to estimate the number of cells showing membranous staining in the tissue section as well as the intensity of the staining [62]. Membranous staining in the invasive component of specimen is scored on a semi-quantitative scale. According to the American Society of Clinical oncology (ASCO) and the College of American Pathologists (CAP) recommendations for HER2 testing in breast cancer published in 2013, HER2 expression is scored as 0 (no staining or weak/incomplete membrane staining in ≤10% of tumor cells), 1+ (weak, incomplete membrane staining in >10% of tumor cells), 2+ (strong, complete membrane staining in ≤10% of tumor cells or weak/moderate and/or incomplete membrane staining in >10% of tumors cells) or 3+ (strong, complete, homogeneous membrane staining in >10% of tumor cells) [61]. In clinical practice, HER2 immunohistochemical status is evaluated as negative if the immunohistochemical score is 0 or 1+, equivocal is the score is 2+, and positive if the score is 3+. Patients with a positive HER2 status at the IHC are eligible for targeted therapy with HER2 inhibitors. The IHC 2+ category is considered borderline and confirmatory testing using an alternative assay (fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods, see Section 2.2.2) is required for final determination.
\nIHC is an easy and relatively inexpensive method [63]. However, this technique can be affected by numerous factors, including warm/cold ischemic time [64], delay and duration of fixation [65], and antibody used [66, 67]. Moreover, since the interpretation of results is based on semiquantitative scoring, this technique is prone to interobserver variability and therefore to substantial discrepancies in the IHC results, particularly for cases scoring 2+ [68].
\nAs mentioned before, HER2 receptor is composed of an extracellular domain (ECD), a transmembrane domain, and an intracellular domain with tyrosine kinase activity. The HER2 ECD can be cleaved from the HER2 full-length receptor through matrix metalloproteases and released into the serum [69]. HER2 ECD levels present in serum can be measured using an enzyme-linked immunosorbent assay (ELISA). HER2 ECD is detected using two antibodies that recognize two specific epitopes of the antigen. Several commercially available ELISA assays received FDA approval: the automated ELISA assay Immuno-1 (Siemens Healthcare Diagnostics, Tarrytown, NY), the manual ELISA assay (Siemens Healthcare Diagnostics) in 2000, and the automated ELISA assay ADVIA Centaur (Siemens Healthcare Diagnostics) in 2003 [70].
\nAlthough some studies suggest that HER2 ECD levels measured in patient’s serum could be used as a biomarker for the monitoring of the disease course and the response of the patient to therapy, the clinical use of the ELISA assay for the evaluation of the HER2 ECD has not yet been widely implemented [71, 72]. This is mainly due to the fact that studies that analyzed the association between HER2 ECD levels and prognostic and predictive factors in breast cancer patients reported conflicting results, depending on which cutoff value was considered or which assay was used [71].
\nELISA is an easy and fast method. In addition, given that HER2 ECD can be measured directly in serum, ELISA can be used to monitor the dynamic changes of HER2 status following treatment or over the course of the disease progression [71]. Results obtained by ELISA, however, might not be reliable if the serum samples are from patients under treatment, as trastuzumab present in the patient’s serum might compete with the two antibodies used in the assay.
\nThe FISH technique is a cytogenetic technique that uses fluorescent probes to target specific DNA sequences in FFPE tissue samples [73]. FISH is effectuated either as a single-color assay (HER2 probe only) to evaluate HER2 gene copies per nucleus or as a dual-color assay using differentially labeled HER2 and chromosome 17 centromere (chromosome enumeration probe 17, CEP17) probes simultaneously. The dual-color assay allows the determination of the HER2/CEP17 ratio [74]. The HER2/CEP17 ratio is often regarded as a better reflection of the HER2 amplification status, as the latter may be influenced by abnormal chromosome 17 copy number (mainly polysomy) [75].
\nThe HER2 gene locus on chromosome 17 is recognized by the HER2 probe, which is labeled with a fluorophore (orange as example). The α satellite DNA sequence located at the centromeric region of chromosome 17 is recognized by a fluorophore-labeled chromosome 17 centromere probe (green as example). Nuclei are then counterstained with 4,6′-diamino-2-phenylindole (DAPI). Fluorescent hybridization signals can be visualized using a fluorescence microscope equipped with appropriate filters (for example Spectrum Orange for locus-specific probe HER2, Spectrum Green for centromeric probe 17, and the UV filter for the DAPI nuclear counterstain) [76].
\nThree FISH assay kits have been approved by the FDA for the determination of the HER2 gene amplification in breast cancer specimens: the single-probe INFORM HER2 FISH DNA kit (Ventana Medical Systems), the dual-probe PathVysion HER-2 DNA probe kit (Abbott Molecular, Des Plaines, IL), and the dual-probe HER2 FISH PharmDx kit (DAKO).
\nAccording to the 2013 ASCO/CAP guidelines, a case is evaluated as amplified when the mean HER2 gene copy number is ≥6 signals/nucleus or HER2/CEP17 ratio is ≥2.0, else as equivocal if mean HER2 gene copy number is ≥4 and <6 signals/nucleus, and else as non-amplified when the mean HER2 gene copy number is <4 signals/nucleus. In order to adequately evaluate HER2 status, a minimum of 20 tumor cell nuclei are counted in at least two invasive tumor areas. For equivocal FISH specimens, results are confirmed by counting 20 additional cells [61]. Moreover, the equivocal category requires reflex testing with the alternative assay (IHC) on the same specimen for final determination. Reflex testing can also be performed using IHC or ISH methods on an alternative specimen. If specimen is evaluated as equivocal, even after reflex testing, the oncologist may consider targeted treatment.
\nAlthough still matter of debate, several researchers consider FISH as being more accurate and reliable than IHC in the assessment of HER2 status in breast cancer specimens [77, 78, 79, 80]. In addition, given that DNA is more stable than protein, preanalytical factors have less impact on assay results compared with IHC [81]. Although the FISH technique yields results that are considered more objective and quantitative than immunohistochemical scoring [73, 82], this method is nine times more time-consuming [83] and three times more expensive compared with IHC [84]. In addition, costly equipment is required for signal detection [67]. The FISH assay can be interpreted only by well-trained personnel, as distinguishing invasive breast cancer from breast carcinoma in situ under fluorescence is arduous [85].
\nMoreover, fluorescence signal counting is time consuming. To overcome this limitation, image analysis software for the automated assessment of fluorescence signals has been developed. Several investigators have reported an excellent concordance between HER2/CEP17 ratios calculated through manual counting and those obtained with automated image analysis system [86, 87, 88]. Some image analysis systems has been approved by the FDA for the automated determination of HER2 gene amplification: the Metafer (MetaSystems, Altlussheim, Germany) and the Ariol HER2/neu FISH (Applied Imaging, San Jose, CA). Furthermore, this software allows the storing of captured images [86].
\nGiven that FISH technology have some limitations, alternative ISH methods have been developed for the assessment of HER2 gene amplification in breast cancer specimens. Similar to FISH, these methods allow the quantification of HER2 gene copy number within tumor cell nuclei in FFPE tissues using a DNA probe that specifically recognizes specific DNA sequences. However, whereas the FISH assay is performed with DNA probes that are coupled to a fluorescent detection system, these alternative ISH methods are performed with probes that are coupled to chromogenic (chromogenic ISH [CISH]), or silver detection system (silver-enhanced ISH [ISH]), or a combination of CISH and SISH (bright-field double ISH [BDISH]) [89]. Similar to FISH, ISH methods are performed either as single-color assay or as a dual-color assay.
\nSince visualization is achieved using other reactions than fluorescence-labeled probe, signals can be evaluated using a standard bright-field microscope, allowing the simultaneous analysis of HER2 gene amplification and morphologic features of tissues. Moreover, contrary to fluorescent signals that fade over time, bright-field ISH signals are permanent [90]. Here after, we will briefly describe the bright-field ISH methods that are used in clinics.
\nCISH allows the visualization of target genes in breast cancer tissue sections through peroxidase enzyme-labeled probes [90]. The single-color CISH assay (SPOT-Light HER2 CISH kit; Life Technologies, Carlsbad, CA), and the dual-color CISH assay (HER2 CISH PharmDx kit; Dako) received FDA approval in 2008 and 2011, respectively [61].
\nWith the single-color CISH assay, only the absolute HER2 gene copy number is evaluated. The hybridized HER2 probe is visualized by DAB as chromogen. HER2 gene copies are recognizable as brown chromogenic reaction product signals within nuclei. Slides are then counterstained with hematoxylin [82, 91, 92]. HER2 signals are recognizable either as large brownish signal clusters or as numerous individual brownish small signals [92]. Cases with low-level amplification show six to 10 signals per nucleus in more than 50% of breast cancer cells, whereas high-level amplification cases are characterized by a mean HER2 gene copy number of more than 10 or by large gene copy clusters in more than 50% of breast cancer cell nuclei [92, 93].
\nThe dual-color CISH assay allows the simultaneous visualization of the HER2 and CEP17 probes on the same slide [94]. HER2 probes are visualized using a chromogen (green as example), whereas CEP17 probes are visualized using another chromogen (red as example). Slides are then counterstained with hematoxylin. Results obtained by dual-color CISH are reported as dual-color FISH [61].
\nThe CISH assay is twice cheaper [72] and 1.2 times faster [82] comparatively to FISH. Furthermore, since the CISH assay allows an easier identification of the invasive component compared with FISH, evaluation of CISH signals is less time-consuming than FISH [82, 94]. In addition, tumor heterogeneity is promptly recognizable, even at low magnification [95]. Moreover, the dual-color assay can be performed on an automated slide stainer, improving the reproducibility of the assay [96]. However, the assessment of HER2 gene copy number can be arduous in tumor regions showing high-level amplification, since overlapping dots lead to formation of signal clusters that are difficult to evaluate [94]. In addition, technical problems, including under- or overfixation, over- or underdigestion of tissue samples can lead to inaccurate results or loss of signals [91, 93].
\nSISH is an automated enzyme metallography assay, in which an enzyme reaction is used to selectively deposit metallic silver from solution at the reaction site to produce a black staining [97]. All steps of the assay are performed on the Ventana BenchMark XT automated slide stainer [98, 99]. HER2 and chromosome 17 analysis is performed on sequential slides [98, 99]. As previously mentioned, HER2 and CEP17 probes are visualized through the process of enzyme metallography. During the process, silver precipitation is deposited in the nucleus, and HER2 or CEP17 signals are visualized as black dots within cell nuclei [99]. Similar to the FISH assay, HER2 gene amplification status assessed by SISH is reported as a HER2/CEP17 ratio, according to the ASCO/CAP guidelines [61].
\nGiven that the SISH assay is fully automated, this technique is six times faster to perform than the FISH assay [99]. In addition, black SISH signals are easier to evaluate compared with other bright-field ISH techniques [100, 101]. However, to correct for chromosome 17 aneusomy, the hybridization of a further section is required for separate assessment of CEP17 copy number [100].
\nBright-field double ISH (BDISH) or dual-color in situ hybridization (dual ISH) is a fully automated bright-field ISH assay for the simultaneous determination of HER2 and CEP17 signals on the same FFPE breast cancer tissue sections [100]. This assay combines the visualization of HER2 gene copies through the deposition of metallic silver particles, similar to the mono-color SISH procedure, with the detection of CEP17 copies with a red chromogen, similar to the CISH assay [102]. HER2 signals are visualized as discrete black spots and the CEP17 signals as red spots in the nuclei. Slides are then counterstained with hematoxylin [100]. HER2 gene amplification status assessed by BDISH is reported as a HER2/CEP17 ratio, according to the ASCO/CAP guidelines.
\nThis technique is very pertinent especially for cases displaying chromosome 17 aneusomy or intratumoral heterogeneity, as it allows the simultaneous visualization of both HER2 and CEP17 probes on the same slide [100]. Furthermore, as the HER2 signals and CEP17 signals differ in color and size (HER2 black spots are smaller than CEP17 red spots), both signals can be distinguished from each other, even though they colocalize within cell nuclei [100]. Moreover, since this assay is completely automated, results are available within 6 h, in addition of being more reproducible, as risk of human errors are diminished [101]. The BDISH assay presents the same disadvantages as CISH and SISH.
\nRecently, new FISH assays have been developed for the evaluation of HER2 gene amplification in breast cancer specimens, including instant-quality FISH (IQFISH), which received FDA approval, and automated HER2 FISH. In analogy to conventional FISH, these new assays allow the quantitative determination of HER2 gene amplification. The IQFISH assay is performed in the same way as manual FISH, with the exception of the hybridization buffer (IQFISH buffer), which considerably reduces the time required for the hybridization step (16 times faster) and therefore the total assay time [103, 104]. Moreover, while hybridization buffer provided in conventional FISH assay contain the toxic formamide, the IQFISH buffer is nontoxic [103]. Compared to conventional FISH, automated FISH is less expensive, since the full automation of the assay requires less human intervention [105]. Furthermore, automated FISH enables faster processing of samples and recording [105].
\nPolymerase chain reaction (PCR) is a technique used for the detection of DNA samples through the exponential amplification of target DNA sequences.
\nReverse transcription PCR (RT-PCR) assay allows the quantification of mRNA and can be used for the evaluation of HER2 expression in breast cancer specimens in both FFPE and frozen tissues [106, 107]. Extracted mRNA is at first reverse transcribed into complementary DNA (cDNA). cDNA is then measured by quantitative PCR (qPCR). The relative quantitation of HER2 gene expression is evaluated comparing the target gene expression with that of housekeeping genes. The relative HER2 gene expression measured in samples is then normalized to a calibrator obtained by mixing RNA from several normal breast tissue specimens. Of note, the Oncotype Dx (Genomic Health, Redwood City, CA) assay is a test based on RT-PCR technology and is used to analyze the expression of 21 genes involved in breast cancer biology, such as HER2, ER, and PR. This assay is used to predict the likelihood of breast cancer recurrence in patients with early-stage, node-negative, ER-positive breast cancer [106].
\nRT-PCR has a large dynamic range, in addition of being a quantitative method. PCR results, however, are often associated with false-negative results due to dilution of amplified tumor cells with surrounding nonamplified stromal cells [108, 109]. In addition, the evaluation of HER2 status at the mRNA level by RT-PCR using FFPE tissues can be problematic, as mRNA integrity can be damaged by several factors, including tissue fixation and storage time [110].
\nHER2 is a prognostic marker in breast cancer. HER2 overexpression and HER2 gene amplification, which occur in 15–20% of breast cancer patients, cause aberrant constitutive activation of the signaling pathway. This leads to uncontrolled and unregulated cell growth and correlates with poor outcome of HER2-positive breast cancer patients.
\nIn addition, HER2-positive status is considered a predictive marker of response to HER2-targeted drugs, including trastuzumab and lapatinib [111]. Considering the clinical and economic implications of targeted anti-HER2 treatments, reliable HER2 test results are essential. False negative results would deny the patients access to the potential benefits of trastuzumab, whereas false positive results would expose patients to the potential cardiotoxic side effects of this expensive agent without experiencing any therapeutic advantages [89].
\nAlthough several techniques have obtained FDA approval for the HER2 assessment in breast cancer specimens, the ASCO/CAP guidelines recommend performing IHC or ISH methods to determine HER2 status in breast cancer. The optimal method for evaluating HER2 status in breast cancer specimens, however, is still matter of debate, since each method is characterized by its own advantages and disadvantages. Therefore, emphasis must be put on standardization of procedures and quality control assessment of already existing methods. Also, development of new accurate assays should be promoted. Moreover, large clinical trials are needed to identify the technique that most reliably predicts a positive response to HER2 inhibitors.
\nDF received doctoral fellowships from the Fonds de recherche du Québec—Santé (FRQS) and the Laval University Cancer Research. CD is a recipient of the Canadian Breast Cancer Foundation-Canadian Cancer Society Capacity Development award (award #703003) and the FRQS Research Scholar.
\nThe authors have no conflicts of interests to declare.
The authors have no other declarations.
\nHER2 | Human epidermal growth factor receptor 2 |
GRB7 | Growth factor receptor bound protein 7 |
ESR1 | Estrogen Receptor 1 |
PGR | Progesterone Receptor |
FDA | Food and Drug Administration |
EGFR | Epidermal growth factor receptor |
IHC | Immunohistochemistry |
FISH | Fluorescence in situ hybridization |
ERBB2 | erb-b2 receptor tyrosine kinase 2 |
HER3 | Human epidermal growth factor receptor 3 |
HER4 | Human epidermal growth factor receptor 4 |
ATP | Adenosine triphosphate |
ECD | extracellular domain |
EGF | Epidermal growth factor |
EPG | Epigen |
TGFα | Transforming growth factor α |
PI3K | Phosphatidylinositol 3′-kinase |
ERK | Extracellular signal-regulated kinase |
MAPK | Mitogen-activated protein kinase |
FGFR | Fibroblast growth factor receptor |
IR | Insulin Receptor |
VEGFR | Vascular Endothelial Growth Factor Receptor |
Cdk | Cyclin-dependent kinase |
FFPE | Formalin-fixed, paraffin-embedded |
DAB | 3,3′-diaminobenzidine tetrahydrochloride |
ASCO | American Society of Clinical Oncology |
CAP | College of American Pathologists |
ELISA | Enzyme-linked immunosorbent assay |
CEP17 | Chromosome enumeration probe 17 |
DAPI | 4,6′-diamino-2-phenylindole |
ISH | in situ hybridization |
CISH | Chromogenic in situ hybridization |
SISH | Silver-enhanced in situ hybridization |
BDISH | Bright-field double ISH |
PCR | polymerase chain reaction |
RT-PCR | Reverse transcription PCR |
cDNA | Complementary DNA |
qPCR | Quantitative PCR |
Authors are listed below with their open access chapters linked via author name:
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