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Epithelial-Mesenchymal Transition in Tumor Microenvironment Induced by Hypoxia

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Görkem Eskiizmir and Erdoğan Özgür

Submitted: 26 February 2018 Reviewed: 15 May 2018 Published: 05 November 2018

DOI: 10.5772/intechopen.78717

Cancer Metastasis IntechOpen
Cancer Metastasis Edited by Yasemin Basbinar

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Cancer Metastasis

Edited by Yasemin Basbinar and Gizem Calıbası-Kocal

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Abstract

A tumor microenvironment contains various noncancerous cells including adipocytes, fibroblasts, immune and inflammatory cells, neuroendocrine cells, pericytes, vascular and lymphatic endothelial cells, and the extracellular matrix that surrounds cancerous cells. In the tumor microenvironment, cancer cells interact and cross talk with noncancerous cells and orchestrate different mechanisms of cancer such as tumorigenesis, angiogenesis, and metastasis. Moreover, the expansive nature of cancer cells and chaotic angiogenesis affect microcirculation as well as alter the oxygen concentration progressively. Hypoxia, a key player in the multistep process of cancer metastasis, is important in different regions of the tumor microenvironment. Hypoxia may transform cancer cells to become more aggressive and invasive by triggering overexpression of several hypoxia-related factors that activate epithelial-mesenchymal transition (EMT). Herein, the current knowledge of how hypoxia-driven EMT is presented in the tumor microenvironment of solid cancers is discussed.

Keywords

  • cancer
  • cancer metastasis
  • epithelial-mesenchymal transition
  • hypoxia
  • tumor microenvironment

1. Tumor microenvironment: current perspective

The tumor microenvironment contains a multinetwork of cells, soluble factors, extracellular matrix (ECM) components, and signaling molecules that surround and neighbor cancer cells. It mediates aberrant tissue function and modulates subsequent progression in solid cancers [1]. In this microenvironment, the main structures are the parenchyma, stroma, growth factors, lymphokines and cytokines, and inflammatory and matrix metalloproteinase enzymes (Figure 1). While cancer cells are located in the parenchyma, noncancerous cells and ECM constitute the stroma. Currently, it is known that noncancerous cells have key roles in several mechanisms of carcinogenesis, tumor progression, and metastatic cascade [2]. Noncancerous cells behave differently in the tumor microenvironment than healthy tissue. However, it is still unclear how noncancerous cells and noncellular components of the tumor niche collaborate and assist cancer cells to acquire invasive and metastatic features.

Figure 1.

A schematic view of the tumor microenvironment.

It is known that chronic inflammation is an important factor in shaping the tumor microenvironment. The major inflammatory cells located in the tumor microenvironment are T lymphocytes, natural killer cells, and tumor-associated macrophages (TAMS). TAMs are important in ECM destruction/restructuring of the tumor microenvironment, tumor cell motility, and triggering angiogenesis. These cells have both tumor-progressive and tumor-suppressive effects.

In the tumor microenvironment, fibroblasts have various roles under inflammatory conditions. However, they attain new characters and called as “carcinoma-associated fibroblasts” after the beginning of the neoplastic process. They constitute 50–70% of the volume of many solid epithelial tumors, such as pancreas, stomach, and breast cancers [3]. In addition, they are particularly effective in carcinogenesis, tumor progression, and metastasis [4, 5]. Studies on carcinoma-associated fibroblasts demonstrated that during the chronic inflammation and wound healing, only activated fibroblasts promote tumor growth. There are hypotheses about the production of cancer-associated fibroblasts. Genetic changes in normal fibroblast or exposure to EMT may directly arise from mesenchymal stem cells [6].

Cancer stem cells (CSCs) are also tumor microenvironment-specific cells. CSCs have been intensively researched recently. Today, we know many cancer types consist CSCs in their microenvironment, which is associated with aggressive tumor biology and treatment resistance. Moreover, CSCs are responsible for immune modulation during the carcinogenesis [7]. In the tumor microenvironment, a unique network has been shown to be created by mainly carcinoma-associated fibroblasts and CSCs with the participant of other noncancerous cells. This network modulates and regulates different mechanisms of the neoplastic processes, such as carcinogenesis, tumor progression, angiogenesis, and metastasis.

Similar to healthy tissue, tumor tissue supplies oxygen and substances from blood and lymphatic vessels. Therefore, angiogenesis is a crucial step for tumor growth [8]. However, due to the rapid growth of tumor tissue, new blood vessel production is usually insufficient. This situation results with decrease of tissue oxygen levels termed as hypoxia. This new condition forces cells to acquire new and devastating behaviors such as resistance to environmental changes, invasiveness, and also metastatic phenotypes via different mechanisms. In this review, we aim to focus on the role of hypoxia and hypoxia-driven EMT in tumor microenvironment from the current perspective.

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2. Hypoxia in tumor microenvironment

Hypoxia is a hallmark of tumor microenvironment. It emerges due to an inadequate blood source, which keeps proliferation cells viable. The cellular machinery uses several mechanisms in response to hypoxia. When a decrease in the level of oxygen develops, changes in numerous transcriptional regulators are altered.

2.1. Hypoxia: definition

Basically, hypoxia refers to the imbalance between the level of oxygen that the tissues require and that can be supplied. It is noteworthy that normoxia describes the “atmospheric” oxygen level which is approximately 20–21% (160 mmHg). However, every healthy tissue has lower and distinct oxygen levels; therefore, physoxia is a better terminology that defines the normal range of oxygen levels in different tissues [9]. The oxygen level of different tissues and cancers is presented in Table 1 [10]. Therefore, hypoxic conditions often occur when the oxygen tension (pO2) decreases lower than 2.5 mmHg, even though tumor oxygen levels are dictated by the initial tissue and tumor microenvironment [11, 12]. Moreover, hypoxic regions are heterogeneously distributed particularly in the locally advanced tumors [13].

Tissue/organ Physoxia (% O2) Cancer Hypoxia (% O2)
Brain 4.6 Brain tumor 1.7
Breast 8.5 Breast cancer 1.5
Cervix 5.5 Cervix cancer 1.2
Kidney (cortex) 9.5 Renal cancer 1.3
Liver 4.0–7.3 Liver cancer 0.8
Lung 5.6 Lung cancer (nonsmall cancer) 2.2
Pancreas 7.5 Pancreas tumor 0.3
Rectal mucosa 3.9 Rectal cancer 1.8

Table 1.

Physoxia and hypoxia of several tissues/organs and cancers.

Cancer cells respond to hypoxia in two ways through apoptosis or resistance and survival, which is driven by the exposure time. If cancer cells are able to survive, they acquire new and unique features. Hypoxic conditions affect the gene transcription, which affords the ability of the cancer to survive through invasiveness, genetic instability, and metastasis. Furthermore, treatment (radiotherapy and/or chemotherapy) resistance may emerge [14]. A hypoxic response is mediated by hypoxia-inducible factors (HIFs), which control many facets of cancer cell viability [15].

2.2. Hypoxia-inducible factors

The HIFs orchestrate the responses to hypoxia in normal and cancer cells. Recently, three subtypes of HIFs have been introduced: HIF-1, -2, and -3. They are heterodimeric complexes and mainly act to mediate cellular processes including angiogenesis, cell proliferation, and tissue remodeling in response to hypoxia. HIFs are composed of basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) proteins including an O2-labile alpha subunit (HIF-1α, -2α, and -3α) and a stable beta subunit (HIF-β). They interact with hypoxia-responsive elements that contain a conserved RCGTG core sequence [16]. HIF-1α was the first introduced prototypic member of HIF family, and has been shown to regulate O2-dependent transcriptional responses [17]. After a while from the discovery of HIF-1α, a new HIF protein, HIF-2α, was introduced by independent research groups [18, 19, 20, 21]. Currently, it is known that HIF-1α is the first biomolecule that responds to acute hypoxia, and HIF-2α is the major regulator under chronic hypoxic conditions. This phenomenon has been referred as the “hypoxic shift” [22]. Holmquist-Mengelbier et al. demonstrated that HIF-1α is active for a short duration particularly under hypoxia or anoxia (O2 level <0.1%). However, HIF-2α is active for a long duration under less severe hypoxia (O2 level <5.0%) [23]. Furthermore, Pietras et al. reported that the activation of HIF-2α may cause aggressive and infiltrative histopathological features under normal oxygen levels, which is termed as “pseudohypoxic phenotype” [24, 25, 26]. Tian et al. reported a correlation between HIF-2α and vascular endothelial growth factor mRNA expression levels in the endothelium [21]. Therefore, HIF-2α overexpression may lead to an increase in chaotic vascularization in the tumor microenvironment. In 2002, HIF-3 was introduced by Makino et al. [27]. Although the functions of HIF-3 are not clear yet, Heikkila et al. indicated that HIF-3 might regulate the activity of other HIF complexes [28].

Hypoxic conditions occur heterogenically in almost all types of solid cancers, which lead to HIF protein overexpression. Under physiologic conditions, HIF-1α is constitutively expressed; however, it is degraded rapidly upon its hydroxylation by prolyl hydroxylases (PHDs) [29]. In contrast, the O2-dependent PHD inhibition develops under hypoxia and HIF-1α protein expression is increased [30]. Under physiological conditions, HIF-1α regulates the expression of important genes that regulate numerous biological processes. In the tumor microenvironment, elevated HIF-α protein expression, which was induced by hypoxia or other oncogenic signals, promotes tumor growth, angiogenesis, and proliferation through the regulation of critical genes (Figure 2). Recent evidence has shown that HIF-1α/-2α can impact tumor development through critical oncoproteins and tumor-suppressor genes such as MYC, p53, and mTOR signaling pathway [31, 32, 33, 34, 35]. HIFs may also promote the immune-suppressive mechanisms that promote apoptotic resistance in the tumor microenvironment [36]. Therefore, HIF-1α overexpression due to pathological hypoxia is generally related to poor prognosis and tumor progression in solid cancer [37, 38]. Moreover, HIFs promote the progression of cancer through EMT induction. During the EMT, carcinoma cells undergo migration and invasion, leading to cancer progression and metastasis [39].

Figure 2.

Regulation of HIF in normoxia and hypoxia. During normoxia, PHD enzymes and FIH take role in hydroxylation of HIF-α. Hydroxylation of HIF-α by PHDs creates a binding site for the Von Hippel-Lindau (VHL), HIF-α-VHL interaction leads to proteasomal degradation. Under hypoxic conditions, PHDs and FIH are inhibited due to lack of oxygen. Inhibition of PHDs and FIH lead to HIF-α stabilization and dimerization with its transcriptional partner HIF-1β. HIF-α-HIF-1β interaction leads to translocation to the nucleus and binding to consensus hypoxia-responsive elements (HRE) within the promoters or enhancers of HIF target genes.

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3. EMT in cancer: an overview

3.1. Epithelial-mesenchymal transition: definition

Epithelial and mesenchymal cells have various functional characteristics. The epithelium is a thin layer which consists of the collection of cells with similar features that have been associated with one to another by cell-to-cell junctions such as tight junctions, adherens junctions, desmosomes, and gap junctions. Epithelium layer is polarized because apical side and the basal side have different properties that are referred as apicobasal polarity. Of note, cell-to-cell junctions consist of cadherins; however, cell-to-basal lamina or ECM junctions consist laminin. Moreover, actin is another cell-to-cell adhesion complex which has strong apicobasal polarity. All of these junctions provide immobility to the epithelium. On the other hand, mesenchymal cells do not have these features and only have focal points that adhere to their neighbor mesenchymal cells. Similar to epithelial cells, adhesions between mesenchymal cells can involve cadherin for cell-to-cell junctions and integrins for adhesion to ECM. However, they do not have junctions for basal lamina. In addition, interstitial collagen and fibronectin are important for the ECM adhesion of the mesenchymal cell. They do not have the same ECM molecules associated with the apical-basolateral surface (Figure 3).

Figure 3.

A schema for epithelial-mesenchymal transition. Loss of epithelial markers and gain of mesenchymal markers during the transition from epithelial phenotype to mesenchymal phenotype.

In 1953, Abercrombie and Heaysman observed that the migration of epithelial cells slows down and they realign when contact each other by forming adhesive junctions [40, 41]. Conversely, mesenchymal cells, particularly fibroblasts, reorient their direction and move away by generating lamellipodia. This process is termed contact inhibition of locomotion. Thereafter, they demonstrated that any defect in contact inhibition of locomotion contributes to the development of invasive and aggressive characters of cancer cells [42, 43, 44]. Today, it is known that contact inhibition of locomotion is important in EMT.

EMT is a complex course where epithelial cells are transformed into mesenchymal cells. It is coordinated by several different influential factors that lead to behavioral changes in epithelial cells. Concisely, epithelial cells lose core properties including the apicobasal polarity, cell adhesion, and increase mesenchymal cell properties during the transition [45, 46].

EMT is a naturally occurring transdifferentiation process and is critical during embryonic development and organogenesis. This phenomenon also occurs during wound healing, tissue regeneration, organ fibrosis, and carcinogenesis. In addition, a post-EMT behavior of a part of cells may include reverse transition, which is referred as the mesenchymal-epithelial transition [47].

The majority of tumors originate from epithelial tissues of lung, colon, breast, pancreas, prostate, bladder, ovary kidney, liver, and head and neck. Currently, EMT is important in cancer progression and metastasis. Epithelial cells may acquire several abilities such as motility, invasion, and malignant features via EMT [48]. Moreover, it is known that inflammation is the key inducer of EMT in cancer progression. Inflammation may trigger a number of signaling pathways involved in carcinogenesis. However, the specific signals that are induced during the pathologic EMT in epithelial cancers remain unclear [49].

3.2. EMT in physiology and diseases

The mechanisms under the induction and progression of EMT vary dramatically, even though motile cells with mesenchymal phenotype develop consequently. EMT is classified into three different subtypes: type-1, -2, and -3. Type-1 EMT (physiologic EMT) is related to implantation, embryogenesis, and organ development. It is impacted by remodeling and diversification of tissue during morphogenesis. Type-1 EMT is not related with inflammation, fibrosis, and systemic dissemination and generally occurs transiently. Type-2 EMT impacts tissue regeneration and fibrosis, and the process depends on continued inflammation in adults. It continues until the underlying injuries or infections are resolved/repaired. Type-2 EMT may produce mesenchymal cells that are activated. Most notably are the myofibroblasts that produce extreme levels of collagen-rich ECM. Type-3 EMT happens in the context of tumor growth/cancer progression and the tumors transform to a mesenchymal phenotype. The type-3 EMT induction is assisted by genomic changes by cancer cells. It may produce cells that have aggressive properties, which promote movement into the bloodstream in order to spread to other organs.

3.2.1. Type-1 EMT

Type-1 EMT is the exchange from epithelial cells to mesenchymal cells in the embryonic phase events such as implantation, embryogenesis, and organ development. After early embryogenic stages, fertilized egg implantation to the endometrium is associated with an EMT [50, 51]. This is the first step of type-1 EMT that is accompanied by embryonic morphogenesis. At the gastrulation stage, EMT continues with the generation of three germ layers and a primitive streak is made in the epiblast layer [52]. The formation of the primitive streak is the most important part of gastrulation. Primitive streak leads to three germ layers. Thereafter, all tissues are generated during organogenesis by cell migration and differentiation. The EMT coordinates almost every stage of this process [53].

At gastrulation level, the EMT is mainly orchestrated by Wnt signaling [54]. Of note, the TGF-β superfamily, including Nodal and Vg1, and FGF receptors are in close relation to Wnt signaling. Moreover, different signaling modalities through BMPs, c-Myb, and msh homeobox 1 (Msx-1) play roles in the regulation of type-1 EMT [55].

3.2.2. Type-2 EMT

Type-2 EMT is the transition of epithelial cells to mesenchymal cells, which occurs during wound healing and fibrosis due to inflammation. It is orchestrated by fibroblasts and inflammatory cells, which release multiple inflammatory molecules, signals, and ECM components such as collagens, laminins, elastin, tenascin, and other matrix molecules. A variety of studies demonstrated an association between EMT and progressive organ fibrosis such as kidney and lung disease [56, 57].

Inflammatory cells and fibroblasts produce proteins such as FSP1, S100 cytoskeletal proteins, α-SMA, and collagen I that develop during the development of organ fibrosis [57]. These proteins have been used as a biomarker for fibrosis of organs, which are undergoing an EMT associated with chronic inflammation. However, epithelial markers, including cytokeratin and E-cadherin, continue to be expressed until they gain a complete fibroblastic phenotype [58]. Rastaldi et al. evaluated the EMT in human renal biopsies of 133 patients with kidney fibrosis. The EMT was detected in the fibrotic kidney based on the staining for cytokeratin, vimentin, α-SMA, and zona occludens 1 (ZO-1) [59]. Kidney fibrosis has been associated with multiple inflammatory cells that induce EMT with various growth factors such as TGF-β, EGF, and FGF-2 [60]. As the role of TGF-β has been determined in kidney fibrosis, several researchers focused on the inhibition of TGF-β using BMP-7 [61]. Morrissey et al. demonstrated that BMP-7 provided the reversal of EMT and repaired tubular structural damage and repopulation of healthy tubular epithelial cells of mice with kidney fibrosis [62].

3.2.3. Type-3 EMT

Type-3 EMT is the transmission of epithelial cells to mesenchymal cells in cancer progression, also known as the “oncogenic epithelial-mesenchymal transition.” Due to its complexity, oncogenic EMT is more complex than physiologic EMT. The role of type-3 EMT has been demonstrated in different cancer cells. For example, breast and prostate cancer cells can be classified as epithelial predominated or mesenchymal predominated [63, 64]. Zajchowski et al. studied different molecules to predict invasiveness of breast cancer by using gene array method and showed that epithelial proteins are related to noninvasiveness, whereas mesenchymal proteins are related to invasiveness [65]. Currently, several in vitro/in vivo studies demonstrated that mesenchymal status leads to an invasive phenotype, motility, and metastasis in cancers.

In solid tumors, loss of E-cadherin [66], cadherin transformation [67], adhesion loss, changes in apicobasal polarity, and tissue architecture modifications have been demonstrated in EMT. In addition, vimentin, N-cadherin, fibronectin, that are the mesenchymal markers, are highly expressed during the EMT [48]. In carcinogenesis and tumor progression, the loss of E-cadherin and increase in the N-cadherin, which is referred as “cadherin switch,” are the most significant indicators of the EMT. Currently, it is known that cadherin switch breaks down cell-to-cell junctions and controls the contact inhibition of locomotion. Moreover, it may modulate signal transduction in metastatic cascade [68]. The association between tumor progression and cadherin switch has been demonstrated in prostate cancer, urothelial bladder carcinoma, and malignant melanoma [67, 69, 70].

In literature, there are evidences that support the idea of “high levels of mesenchymal markers are often related to aggressive tumor behavior and poor prognosis.” In cervix cancers, the correlation between lymph node metastasis and vimentin positivity was also determined [71]. Nevertheless, this correlation has been reported in a small number of cancer types. Therefore, it is hard to mention that vimentin is a definitive predictor of aggressiveness for all cancer types. Ahmad et al. suggested another biomarker for metastatic breast cancer: stromelysin-3. Stromelysin-3 is a matrix metalloproteinase and marker for mesenchymal cells. Breast carcinoma cells that undergo EMT are able to express stromelysin-3, which may partly explain the increased metastatic propensity detected in these tumors [72].

Recently, the genetic and biochemical properties that underlie acquirement of cancer cell invasiveness and metastasis are the major areas of intensive research. Xue and colleagues demonstrated that cancer cells departing HER-2/neu expressed a GFP transgene that was facilitated by FSP-1. Moreover, the low rate of metastasis was detected in FSP-1 null mice [73]. This research provided important evidences for the mechanism of metastasis related to EMT. In addition, Yang et al. reported that tumor cells were able to behave like mesenchymal cells and express mesenchymal markers [74]. Besides the evidences about EMT in the metastatic process, some studies have also shown data on reverse EMT. They suggest that the reversibility of EMT is observed during embryonic development and also during the tumor growth at metastatic side. Tumor cells try to undergo not only growth but also cell differentiation to resemble the originating epithelium. Brabletz et al. demonstrated the similarity of epithelial nature between primary tumor side and metastatic tissue for colorectal cancers [75]. It indicates that the induction of an EMT is likely to be central and crucial for the metastatic cascade and implicates EMT during the colonization process.

3.3. Molecular mechanisms and pathways of EMT

In pathologic or physiologic events, the EMT is triggered and controlled by different signaling pathways. Several transcription factors have been described for the regulation of EMT. Tumor growth factor-β signaling appears to be one of the most important pathways. It generally acts as an epithelial cell proliferation suppressor. However, it may also positively affect the tumor progression and metastasis [76, 77]. TGF-β can induce the EMT via two signaling pathways. The first pathway involves Smad proteins that regulate the action of tumor growth factor-β by affecting ALK-5 receptors. Smad proteins mediate signaling pathway effects on motility of cells [61, 78]. Inhibitory Smad can induce autocrine production of TGF-β, thereby, reinforcing epithelial-mesenchymal transition [79]. Recently, β-catenin and LEF found to be relevant with Smad in PDGF-induced EMT [80]. Currently, it is known that TGF-β/Smad/LEF/PDGF axis has important effects on EMT during cancer progression. The second mechanism for TGF-β-induced EMT is MAPK-dependent pathway [81].

Several studies have demonstrated the association between reduced cancer cell E-cadherin levels and activation of EMT [82, 83]. Eger et al. showed that the cFos oncogene induction in mouse mammary epithelial cells induced the EMT by decreasing E-cadherin [84]. The movement of β-catenin from the cytoplasm to nucleus causes acquisition of mesenchymal phenotype by affecting E-cadherin expression. Nuclear buildup of β-catenin has been shown to reduce E-cadherin expression and acquisition of invasive phenotype [85]. Scarpa et al. described the E-cadherin loss as an activation and contact-dependent cell polarity process via Rac signaling [86]. Currently, it is known that reduced E-cadherin levels are highly correlated with poor prognosis and decrease in survival in various cancers such as hepatocellular carcinoma, nonsmall cell lung, oral, esophageal, gastric, cervix and breast cancer, and bone and soft tissue sarcoma [87, 88, 89, 90, 91, 92, 93, 94, 95].

3.4. EMT in cancer metastasis: guilty or innocent?

Cancer metastasis is a complex multistep process with sequential molecular and cellular events that promote the transformation of cells, intravasation, survival and ultimately extravasation, implantation, growth, and colonization in a new and foreign tissue environment. As mentioned above, several evidences support that EMT has a major role in cancer metastasis. The EMT signifies the first step of the metastatic cascade. During EMT, cancer cells are able to invade adjacent cell layers following the loss of cell-to-cell adhesion and acquiring motility. Principally, the result of cellular motility is similar to the extensive cell migration and tissue reorganization that occurs during the embryogenesis and organogenesis; however, subsequent steps have different and complex events.

After a journey in the bloodstream, cancer cells that can escape from the immune system, extravasate from the circulation in order to implant and proliferate at the target organ, “seed and soil theory.” Thereby, a colony of the primary tumor can regrow by inducing angiogenesis in a foreign and apparently “hostile” background. This process is induced by not only genetic/epigenetic factors but also by the nonneoplastic stromal cells [96]. In vivo studies demonstrated that this development is generally supplemented with partial or complete EMT. Therefore, the induction of EMT results in the acquisition of metastatic properties in different carcinoma cell lines. Main indicators for the acquisition of mesenchymal properties are the high level of mesenchyme-specific proteins [46]. In contrast to many studies, Tarin et al. reported that the acquirement of mesenchymal markers during tumor progression reflects genomic instability. Therefore, they advocated that EMT does not occur in carcinogenesis [97]. However, synchronized and complex gene-expression patterns are required to provide tumor cells with the mesenchymal properties. Moreover, genomic instability may have more important role in the regulation of EMT. For instance, SNAI1 regulates expression of EMT-associated genes in colorectal carcinoma [98].

A significant evidence for EMT during the metastatic process was presented by Yang et al. They reported that cancer cells were able to behave like mesenchymal cells and express α-SMA, FSP1, desmin, and vimentin [74]. Studies that include functional manipulations on EMT process also provide evidences. For instance, depletion of FSP1/S100A4-positive cells in tumors suppresses metastasis [73].

In adenomatous polyposis coli (APC) and β-catenin mutation-positive colorectal cancers, β-catenin levels are predominantly observed in tumor cells localized at invasion. Moreover, tumor cells with nuclear β-catenin seem to have undergone EMT [99]. Regardless of numerous studies, the major problem for the demonstration of the role of EMT in the metastatic cascade is the detection of cancer cells that have undergone EMT in primary human tumors. The markers of EMT indicate epithelial phenotype or mesenchymal phenotype not the EMT in cancer metastasis. Therefore, in vivo studies with more sensitive indicators are required for understanding the role of EMT in cancer metastasis.

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4. A new insight into the mechanisms of hypoxia-induced EMT

Hypoxia is a common situation in tumor microenvironment affecting cancer cell behavior, including progression and metastasis. Currently, it is clearly known that exposure to hypoxic conditions results in HIF-1α overexpression. As mentioned previously, overexpression of HIF-1a is related with promoting EMT for cancer cells. Additionally, it has been demonstrated that hypoxia-induced EMT includes the loss of cell adhesion and cell polarity. It has been observed that hypoxic conditions decrease the E-cadherin expression, but increase N-cadherin expression, a mesenchymal marker [100].

Azab et al. previously demonstrated that multiple myeloma cancer cells cultured in hypoxic conditions and injected into mice were able to spread to the new bone marrow faster than the cells cultured under normoxic conditions [101]. The hypoxia-induced EMT is mainly driven by stabilization and activation of HIF1α. It is controlled by epigenetic changes that result in a loss of tumor-suppressor functions and gain of oncogene functions (Ras, Raf, Src, mTOR, and Myc). Besides hypoxic conditions, the HIF pathway is also regulated by hypoxia-independent manner [102, 103]. Hypoxia-independent HIF-α stabilization and activation happens in response to cytokines, lipopolysaccharide (LPS), and growth factors in EMT mediated by PI3K/AKT/mTOR,29,30 MAPK,41 and NFĸB pathways [104, 105, 106].

HIF-1α regulates hundreds of genes, and not only controls malignant and metastatic cancer cells but is also resistant to treatments. Thus, inhibition of hypoxia-induced EMT or HIF-1α may be promising as an anticancer therapy. Currently, there are many researches ongoing in this field. Besides targeting HIF-1α, another strategy is to block metastasis and target genes downstream of HIF-1α. Kaneko et al. have researched the hypoxia-induced EMT in oral cavity squamous cell carcinoma and showed that hypoxia-induced EMT in oral cavity cancer was improved by GSK3-β phosphorylation via PI3 K/Akt signaling [107]. Jiao and Nan showed that hypoxia-induced EMT and chemoresistance were supplemented with HIF-1α expression and Akt activation. Moreover, they demonstrated that PI3K/Akt and HIF-1α inhibition improved the therapeutic efficacy of hypoxic chemotherapy [108]. Lo Dico et al. reported that miR-675-5p promotes glioma growth through HIF-1α stabilization. Subsequently, they examined miR-675-5p specifically in colon cancer metastasis and demonstrated overexpression contributes to tumor progression through HIF-1α-induced EMT [109, 110].

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5. Conclusion

Hypoxia is a hallmark of cells in the tumor microenvironment and has a major role in the carcinogenesis and metastasis processes. Hypoxia controls many crucial events such as tumor neovascularization, metabolism, cell survival, and cell death. Furthermore, hypoxia causes EMT and CSC-like properties including resistance to treatment. Each step of the cancer adaptive process is regulated by HIF, NFĸB, PI3K, and MAPK pathways. Understanding the impact of hypoxia and clarifying the hypoxia-induced responses and signaling modalities may pave the way to achieve important steps against cancer via hypoxia/HIF-targeted treatments.

References

  1. 1. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015;13:45
  2. 2. Ran M, Witz IP. Tumor-associated immunoglobulins. Enhancement of syngeneic tumors by IgG2-containing tumor eluates. International Journal of Cancer. 1972;9:242-247
  3. 3. Desmouliere A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. International Journal of Developmental Biology. 2004;48:509-517
  4. 4. Xing F, Saidou J, Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Frontiers in Bioscience. (Landmark Ed). 2010;15:166-179
  5. 5. Wheeler SE, Shi H, Lin F, Dasari S, Bednash J, Thorne S, et al. Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models. Head Neck. 2014;36:385-392
  6. 6. Ostman A, Augsten M. Cancer-associated fibroblasts and tumor growth--bystanders turning into key players. Current Opinion in Genetics & Development. 2009;19:67-73
  7. 7. Birnie R, Bryce SD, Roome C, Dussupt V, Droop A, Lang SH, et al. Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions. Genome Biology. 2008;9:R83
  8. 8. Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, et al. Type-2 pericytes participate in normal and tumoral angiogenesis. American Journal of Physiology-Cell Physiology. 2014;307:C25-38
  9. 9. McKeown SR. Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. The British Journal of Radiology. 2014;87:20130676
  10. 10. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 2015;3:83-92
  11. 11. Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. Journal of Cellular and Molecular Medicine. 2011;15:1239-1253
  12. 12. Vaupel P, Hockel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal. 2007;9:1221-1235
  13. 13. Vaupel P. Prognostic potential of the pre-therapeutic tumor oxygenation status. Advances in Experimental Medicine and Biology. 2009;645:241-246
  14. 14. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nature Reviews Cancer. 2008;8:425-437
  15. 15. Guillemin K, Krasnow MA. The hypoxic response: huffing and HIFing. Cell. 1997;89:9-12
  16. 16. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Molecular Cell. 2010;40:294-309
  17. 17. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the USA. 1995;92:5510-5514
  18. 18. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proceedings of the National Academy of Sciences of the USA. 1997;94:4273-4278
  19. 19. Flamme I, Frohlich T, von Reutern M, Kappel A, Damert A, Risau W. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mechanisms of Development. 1997;63:51-60
  20. 20. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. Journal of Biological Chemistry. 1997;272:8581-8593
  21. 21. Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes & Development. 1997;11:72-82
  22. 22. Koh MY, Powis G. Passing the baton: the HIF switch. Trends in Biochemical Sciences.. 2012;37:364-372
  23. 23. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell. 2006;10:413-423
  24. 24. Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S, et al. High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. Journal of Pathology. 2008;214:482-488
  25. 25. Pietras A, Hansford LM, Johnsson AS, Bridges E, Sjolund J, Gisselsson D, et al. HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proceedings of the National Academy of Sciences of the USA. 2009;106:16805-16810
  26. 26. Pietras A, Johnsson AS, Pahlman S. The HIF-2alpha-driven pseudo-hypoxic phenotype in tumor aggressiveness, differentiation, and vascularization. Current Topics in Microbiology and Immunology. 2010;345:1-20
  27. 27. Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. Journal of Biological Chemistry. 2002;277:32405-32408
  28. 28. Heikkila M, Pasanen A, Kivirikko KI, Myllyharju J. Roles of the human hypoxia-inducible factor (HIF)-3alpha variants in the hypoxia response. Cellular and Molecular Life Sciences. 2011;68:3885-3901
  29. 29. Semenza GL. Targeting HIF-1 for cancer therapy. Nature Reviews Cancer. 2003;3:721-732
  30. 30. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271-275
  31. 31. An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM. Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature. 1998;392:405-408
  32. 32. Dang CV, Kim JW, Gao P, Yustein J. The interplay between MYC and HIF in cancer. Nature Reviews Cancer. 2008;8:51-56
  33. 33. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11:335-347
  34. 34. Lavin MF, Gueven N. The complexity of p53 stabilization and activation. Cell Death & Differentiation. 2006;13:941-950
  35. 35. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Molecular Cell. 2010;40:310-322
  36. 36. Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology. 2014;143:512-519
  37. 37. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. Journal of the National Cancer Institute. 2001;93:309-314
  38. 38. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Research. 1999;59:5830-5835
  39. 39. Bates RC, Mercurio AM. The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biology & Therapy. 2005;4:365-370
  40. 40. Abercrombie M, Heaysman JE. Observations on the social behaviour of cells in tissue culture. I. Speed of movement of chick heart fibroblasts in relation to their mutual contacts. Experimental Cell Research. 1953;5:111-131
  41. 41. Abercrombie M, Heaysman JE. Observations on the social behaviour of cells in tissue culture. II. Monolayering of fibroblasts. Experimental Cell Research. 1954;6:293-306
  42. 42. Abercrombie M, Heaysman JE. Invasiveness of sarcoma cells. Nature. 1954;174:697-698
  43. 43. Abercrombie M, Heaysman JE, Karthauser HM. Social behaviour of cells in tissue culture. III. Mutual influence of sarcoma cells and fibroblasts. Experimental Cell Research. 1957;13:276-291
  44. 44. Abercrombie M. Contact inhibition and malignancy. Nature. 1979;281:259-262
  45. 45. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. Journal of Clinical Investigation. 2003;112:1776-1784
  46. 46. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. Journal of Cell Biology. 2006;172:973-981
  47. 47. Locascio A, Nieto MA. Cell movements during vertebrate development: integrated tissue behaviour versus individual cell migration. Current Opinion in Genetics & Development. 2001;11:464-469
  48. 48. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer. 2002;2:442-454
  49. 49. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. Journal of Clinical Investigation. 2009;119:1438-1449
  50. 50. Bischof P, Aplin JD, Bentin-Ley U, Brannstrom M, Casslen B, Castrillo JL, et al. Implantation of the human embryo: research lines and models. From the implantation research network ‘Fruitful’. Gynecologic and Obstetric Investigation. 2006;62:206-216
  51. 51. Vicovac L, Aplin JD. Epithelial-mesenchymal transition during trophoblast differentiation. Acta Anat (Basel). 1996;156:202-216
  52. 52. Hay ED. Role of cell-matrix contacts in cell migration and epithelial-mesenchymal transformation. Cell Differentiation and Development. 1990;32:367-375
  53. 53. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nature Reviews Molecular Cell Biology. 2006;7:131-142
  54. 54. Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A. Requirement for Wnt3 in vertebrate axis formation. Nature Genetics. 1999;22:361-365
  55. 55. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation. 2009;119:1420-1428
  56. 56. Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Piccoli P, et al. Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. American Journal of Pathology. 2003;162:1495-1502
  57. 57. Ivanova L, Butt MJ, Matsell DG. Mesenchymal transition in kidney collecting duct epithelial cells. American Journal of Physiology-Renal Physiology. 2008;294:F1238-1248
  58. 58. Okada H, Strutz F, Danoff TM, Kalluri R, Neilson EG. Possible mechanisms of renal fibrosis. Contributions to Nephrology. 1996;118:147-154
  59. 59. Rastaldi MP, Ferrario F, Giardino L, Dell’Antonio G, Grillo C, Grillo P, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney International. 2002;62:137-146
  60. 60. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney International. 2002;61:1714-1728
  61. 61. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Medicine. 2003;9:964-968
  62. 62. Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S. Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. Journal of the American Society of Nephrology. 2002;13(Suppl 1):S14-21
  63. 63. Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science. 2002;296:1046-1049
  64. 64. Cunha GR, Hayward SW, Wang YZ. Role of stroma in carcinogenesis of the prostate. Differentiation. 2002;70:473-485
  65. 65. Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A, et al. Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Research. 2001;61:5168-5178
  66. 66. Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. The International Journal of Developmental Biology. 2004;48:365-375
  67. 67. Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ, et al. Cadherin switching in human prostate cancer progression. Cancer Research. 2000;60:3650-3654
  68. 68. Hazan RB, Qiao R, Keren R, Badano I, Suyama K. Cadherin switch in tumor progression. Annals of the New York Academy of Sciences. 2004;1014:155-163
  69. 69. Bryan RT, Tselepis C. Cadherin switching and bladder cancer. Journal of Urology. 2010;184:423-431
  70. 70. Lade-Keller J, Riber-Hansen R, Guldberg P, Schmidt H, Hamilton-Dutoit SJ, Steiniche T. E- to N-cadherin switch in melanoma is associated with decreased expression of phosphatase and tensin homolog and cancer progression. British Journal of Dermatology. 2013;169:618-628
  71. 71. Gilles C, Polette M, Piette J, Delvigne AC, Thompson EW, Foidart JM, et al. Vimentin expression in cervical carcinomas: association with invasive and migratory potential. The Journal of Pathology. 1996;180:175-180
  72. 72. Ahmad A, Hanby A, Dublin E, Poulsom R, Smith P, Barnes D, et al. Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression. The American Journal of Pathology. 1998;152:721-728
  73. 73. Xue C, Plieth D, Venkov C, Xu C, Neilson EG. The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Research. 2003;63:3386-3394
  74. 74. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental Cell. 2008;14:818-829
  75. 75. Brabletz T, Jung A, Kirchner T. Beta-catenin and the morphogenesis of colorectal cancer. Virchows Arch. 2002;441:1-11
  76. 76. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nature Reviews Cancer. 2006;6:506-520
  77. 77. Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Current Biology. 1998;8:1243-1252
  78. 78. Piek E, Moustakas A, Kurisaki A, Heldin CH, ten Dijke P. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci. 1999;112( Pt 24):4557-4568
  79. 79. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genetics. 2001;29:117-129
  80. 80. Yang L, Lin C, Liu ZR. P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell. 2006;127:139-155
  81. 81. Nawshad A, Lagamba D, Polad A, Hay ED. Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs. 2005;179:11-23
  82. 82. Edelman GM, Gallin WJ, Delouvee A, Cunningham BA, Thiery JP. Early epochal maps of two different cell adhesion molecules. Proceedings of the National Academy of Sciences of the USA. 1983;80:4384-4388
  83. 83. Tepass U, Truong K, Godt D, Ikura M, Peifer M. Cadherins in embryonic and neural morphogenesis. Nature Reviews Molecular Cell Biology. 2000;1:91-100
  84. 84. Eger A, Stockinger A, Schaffhauser B, Beug H, Foisner R. Epithelial mesenchymal transition by c-Fos estrogen receptor activation involves nuclear translocation of beta-catenin and upregulation of beta-catenin/lymphoid enhancer binding factor-1 transcriptional activity. Journal of Cell Biology. 2000;148:173-188
  85. 85. Kim K, Lu Z, Hay ED. Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biology International. 2002;26:463-476
  86. 86. Scarpa E, Szabo A, Bibonne A, Theveneau E, Parsons M, Mayor R. Cadherin Switch during EMT in Neural Crest Cells Leads to Contact Inhibition of Locomotion via Repolarization of Forces. Developmental Cell. 2015;34:421-434
  87. 87. Chen J, Zhao J, Ma R, Lin H, Liang X, Cai X. Prognostic significance of E-cadherin expression in hepatocellular carcinoma: a meta-analysis. PLoS One. 2014;9:e103952
  88. 88. Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. The American Journal of Pathology. 1998;153:333-339
  89. 89. Li Z, Yin S, Zhang L, Liu W, Chen B. Prognostic value of reduced E-cadherin expression in breast cancer: a meta-analysis. Oncotarget. 2017;8:16445-16455
  90. 90. Luo SL, Xie YG, Li Z, Ma JH, Xu X. E-cadherin expression and prognosis of oral cancer: a meta-analysis. Tumor Biology. 2014;35:5533-5537
  91. 91. Peng J, Qi S, Wang P, Li W, Song L, Liu C, et al. Meta-analysis of downregulated E-cadherin as a poor prognostic biomarker for cervical cancer. Future Oncology. 2016;12:715-726
  92. 92. Wang N, He YL, Pang LJ, Zou H, Liu CX, Zhao J, et al. Down-regulated E-cadherin expression is associated with poor five-year overall survival in bone and soft tissue sarcoma: results of a meta-analysis. PLoS One. 2015;10:e0121448
  93. 93. Xing X, Tang YB, Yuan G, Wang Y, Wang J, Yang Y, et al. The prognostic value of E-cadherin in gastric cancer: a meta-analysis. International Journal of Cancer. 2013;132:2589-2596
  94. 94. Xu XL, Ling ZQ, Chen SZ, Li B, Ji WH, Mao WM. The impact of E-cadherin expression on the prognosis of esophageal cancer: a meta-analysis. Dis Esophagus. 2014;27:79-86
  95. 95. Yang YL, Chen MW, Xian L. Prognostic and clinicopathological significance of downregulated E-cadherin expression in patients with non-small cell lung cancer (NSCLC): a meta-analysis. PLoS One. 2014;9:e99763
  96. 96. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275-292
  97. 97. Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Research. 2005;65:5996-6000; discussion 6000-5991
  98. 98. De Craene B, Gilbert B, Stove C, Bruyneel E, van Roy F, Berx G. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Research. 2005;65:6237-6244
  99. 99. Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Current Opinion in Cell Biology. 2007;19:150-158
  100. 100. Bao B, Ahmad A, Kong D, Ali S, Azmi AS, Li Y, et al. Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF. PLoS One. 2012;7:e43726
  101. 101. Azab AK, Hu J, Quang P, Azab F, Pitsillides C, Awwad R, et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood. 2012;119:5782-5794
  102. 102. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. Journal of Biological Chemistry. 1999;274:32631-32637
  103. 103. van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochemical Journal. 2008;412:477-484
  104. 104. Agani F, Jiang BH. Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Current Cancer Drug Targets. 2013;13:245-251
  105. 105. Kilic-Eren M, Boylu T, Tabor V. Targeting PI3K/Akt represses Hypoxia inducible factor-1alpha activation and sensitizes Rhabdomyosarcoma and Ewing’s sarcoma cells for apoptosis. Cancer Cell International. 2013;13:36
  106. 106. Seta KA, Spicer Z, Yuan Y, Lu G, Millhorn DE. Responding to hypoxia: lessons from a model cell line. Science’s STKE. 2002;2002:re11
  107. 107. Kaneko T, Dehari H, Sasaki T, Igarashi T, Ogi K, Okamoto JY, et al. Hypoxia-induced epithelial-mesenchymal transition is regulated by phosphorylation of GSK3-beta via PI3 K/Akt signaling in oral squamous cell carcinoma. Oral Surgery, Oral Medicine, Oral Pathology, and Oral Radiology. 2016;122:719-730
  108. 108. Jiao M, Nan KJ. Activation of PI3 kinase/Akt/HIF-1alpha pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma. International Journal of Oncology. 2012;40:461-468
  109. 109. Costa V, Lo Dico A, Rizzo A, Rajata F, Tripodi M, Alessandro R, et al. MiR-675-5p supports hypoxia induced epithelial to mesenchymal transition in colon cancer cells. Oncotarget. 2017;8:24292-24302
  110. 110. Lo Dico A, Costa V, Martelli C, Diceglie C, Rajata F, Rizzo A, et al. MiR675-5p Acts on HIF-1alpha to Sustain Hypoxic Responses: A New Therapeutic Strategy for Glioma. Theranostics. 2016;6:1105-1118

Written By

Görkem Eskiizmir and Erdoğan Özgür

Submitted: 26 February 2018 Reviewed: 15 May 2018 Published: 05 November 2018

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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