Tumor development, promotion and ability to spread depend greatly on
tumor microenvironment. Rapid growth accompanied by inadequate angiogenesis is the reason why most solid tumors contain hypoxic regions. Activation of hypoxia signaling pathways stimulates neoangiogenesis, alters tumor metabolism, promotes a more aggressive tumor behavior and significantly affects its responsiveness to therapy. Growing amount of evidence suggest that hypoxia induces transcription of tumor promoting genes leading to increased tumor cell proliferation and metastatic potential. Improved understanding of molecular pathways will enable establishment of useful prognostic and predictive factors, along with more effective treatment options

ANA KULIĆ

LADA BRADIĆ1 BRADIĆ

MARINA BARIĆ1 BARIĆ

NATALIJA DEDIĆ PLAVETIĆ DEDIĆ PLAVETIĆ

STJEPKO PLEŠTINA

English

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PERIODICUM BIOLOGORUM UDC 57:61 VOL. 116, No 4, 361–364, 2014 CODEN PDBIAD  ISSN 0031-5362  Hypoxia in solid tumors: biological responses  to hypoxia and implications on therapy and prognosisAbstractTumor development, promotion and ability to spread depend greatly on tumor microenvironment. Rapid growth accompanied by inadequate angio-genesis is the reason why most solid tumors contain hypoxic regions. Activation of hypoxia signaling pathways stimulates neoangiogenesis, alters tumor me-tabolism, promotes a more aggressive tumor behavior and significantly affects its responsiveness to therapy. Growing amount of evidence suggest that hy-poxia induces transcription of tumor promoting genes leading to increased tumor cell proliferation and metastatic potential. Improved understanding of molecular pathways will enable establishment of useful prognostic and predic-tive factors, along with more effective treatment options.INTRODUCTIONIn addition to being an essential molecule for oxidative phosphoryla-tion in mitochondria, oxygen also functions as an important signaling molecule and regulates a wide range of biological processes, including erythropoiesis, angiogenesis, and cellular differentiation (1). Hypoxic regions are common characteristic of majority of solid neoplasms, result-ing from discordance between high metabolic needs of rapid growing malignant tissues and oxygen supply through structurally and function-ally impaired microvasculature. Recognition of tumor hypoxia and its clinical significance was hampered for a long time by a lack of standard-ized methods for routine measurement of intra-tumor partial oxygen pressure (2, 3). In the past decade, considerable progress has been made in the field of tumor oxygenation and its impact on tumor promotion, and metastatic potential, therapeutic response and prognosis in patients with solid malignant neoplasms (4).Research shows relative resistance of tumorous tissue against ionizing radiation, chemotherapy and other non-surgical treatment modalities (5). Hypoxia is believed to be a key microenvironment factor that in-duces tumor metastasis. It amplifies adaptations that enable tumor cell survival (anaerobic shift, neovascularization, resistance to apoptosis) and, on the other hand stimulates tumor aggressiveness (gene instabil-ity, invasion, metastasis, dedifferentiation) (6).METABOLIC CHANGES OF TUMOR CELLS IN HYPOXIATumor microenvironment is metabolically heterogeneous; cells close to the functioning microvasculature are well oxygenated and dependant NATALIJA DEDIĆ PLAVETIĆ1MARINA BARIĆ1LADA BRADIĆ1ANA KULIĆ2STJEPKO PLEŠTINA11  Department of Oncology, Division of Medical Oncology, University Hospital Center and Zagreb Medical School, Zagreb, Croatia2  Department of Oncology, Division of Pathophysiology and Experimental Oncology, University Hospital Center, Zagreb, CroatiaCorrespondence: Natalija Dedi} Plaveti}, MD, PhD Department of Oncology University Hospital Center Zagreb Ki{pati}eva 12, HR- 10 000 Zagreb, Croatia E-mail: natalija.dedic-plavetic@zg.t-com.hrKey words: hypoxia, solid tumor, angiogenesis, tumor microenvironment, gene expression,  progression, metastasis, resistance to treatmentAbbreviations: VHL  = von Hippel-Lindau HIF = hypoxia-inducible factor HRE = hypoxia-response elements mTOR = mammalian target of rapamycin PI3K = phosphatidylinositol 3-kinase Akt = protein kinase B Tan IIA = tanshinone IIA compound VEGF  = vascular endothelial growth factor VEGFR = vascular endothelial growth factor receptor PET = positron emission tomography LDH = lactate dehydrogenase MCT = monocarboxylate transporter miRs = micro RNA moleculesReceived January 27, 2015.OverviewNatalija Dedić Plavetić et al. Hypoxia in solid tumors362 Period biol, Vol 116, No 4, 2014.on oxidative metabolism, whereby distant cells are poorly oxygenated and glycolysis-dependant. Adaptive changes in cell metabolism of tumor cells involve shift from oxida-tive phosphorylation to glycolysis, increased glycogen synthesis; switch from glucose to glutamine as a major substrate for fatty acid synthesis (1).Cellular response to hypoxia is modulated by a family of ubiquitous transcription factors known as hypoxia in-ducible factors (HIF), comprising HIF-1a, HIF-2a and HIF-3a (Figure 1). Metabolic reprogramming is coordi-nated on a transcription level of hypoxia inducible factor 1 (HIF-1), considered to be a main regulator of oxygen supply and demand (7) (Figure 1).In hypoxic cells HIF-1 increases expression of glucose transporters, glycolytic enzymes (e.g. LDH-A, MCT-4) that stimulate glucose uptake, conversion to lactate and lactate efflux from the cell. On the other hand, well oxy-genated cells express MCT-1 and LDH-B, that mediate lactate transport intracellularly and its conversion into pyruvate needed for oxidative metabolism (8).Role of hypoxia inducible factor (HIF-1)HIF-1 is a heterodimer comprised of HIF-1a and HIF-1b subunits. HIF-1a expression is regulated by oxygen and degrades swiftly in normoxic conditions. On the other hand, hypoxia stabilizes HIF-1a and results in its accumu-lation. HIF-1b is constitutively expressed. However, in certain conditions of adequate oxygenation, HIF-1a expres-sion can increase. HIF-1 in tumor cells can be activated by the loss of function of tumor suppressor genes (e.g. VHL) and/or oncogene gain of function with resulting increase in activity of e.g. PI3K/AKT/mTOR signal pathways (9).Modes of HIF-1 protein level increase are diverse. For example, von Hippel-Lindau protein mutation stabilizes HIF-1a protein, while activation of PI3K/AKT/mTOR signal pathway stimulates HIF-1a mRNA translation. Reactive oxygen and nitrogen species inhibit HIF-1a pro-teasome. Following stabilization of HIF-1a, heterodimer protein activates transcription of numerous genes in-volved in angiogenesis, proliferation, glycolytic tumor metabolism and regulation of cellular pH (9).HIF-1 is a mediator of metabolic alterations that gov-ern tumor progression and resistance to treatment. In-hibitors of HIF or metabolic enzymes can impair tumor cell flexibility and render them more susceptible to anti-neoplastic regimens (10).HIF family also contributes to transactivation of genes that encode micro RNA molecules (miRs). Micro RNAs Figure 1. Hypoxia upregulates various transcription factors. HIF (hypoxia-inducible factor) plays a key role inducing transcription of genes in-volved in tumor progression, angiogenesis, erythropoiesis, metabolism, apoptosis and tissue remodelling.Hypoxia in solid tumors Natalija Dedić Plavetić et al.Period biol, Vol 116, No 4, 2014. 363are small regulatory RNA molecules that bind specific messenger RNA (mRNA) sequences, and thereby inhib-it translation or stimulate their degradation. Many cell types show increased miR-210 expression typical for a hypoxic response (11).HYPOXIA AND CANCER METASTASISMajority of solid tumors have hypoxic areas. Measure-ments of tissue oxygenation in breast cancer have shown correlation between large areas of hypoxic tissue and ex-pression of hypoxic markers detected by immunolocaliza-tion methods. Staining for CAIX and HIF-1a in breast cancer tissues shows high intensity surrounding necrotic areas. In pre-clinical models, efficient deletion of HIF-1a inhibits primary tumor growth, suppresses lung metasta-sis and prolongs survival. Loss of HIF-1a inhibits expres-sion of markers of basal breast cancer phenotype, as well as numerous genes involved in epithelial-mesenchymal transition (12).Expression of numerous genes associated with breast cancer metastasis is increased in hypoxic conditions, correlating with worse outcome (13, 14). Better under-standing of molecular pathways involving hypoxia-stimulated breast cancer metastasis could result in po-tentially beneficial, prognostic as well as therapeutic implications (15, 16).THERAPEUTIC IMPLICATIONS OF TUMOR HYPOXIAEffect of hypoxia to radiotherapy treatmentHIF-1 protein has an important role in tumor resis-tance against radiotherapy treatment, either through post-irradiation protection against neoangiogenesis or through amplified anti-oxidative capacity as a component of gly-colytic tumor metabolism.In preclinical trials, blockage of HIF-1a and tumor glucose metabolism affects tumor microenvironment, stimulates metabolic alterations and sensitizes various solid tumors to radiation. Future research should eluci-date weather HIF-1 inhibitors and inhibitors of glucose metabolism could prove beneficial in clinical practice. Special attention should be focused on effects of HIF-1 inhibition on tumor glycolytic and redox potential. Op-timal timing for introduction of these inhibitors during the treatment course is yet to be established (17).In order to optimize patients suitable for such treat-ment, it is necessary to additionally validate imaging tech-niques for determination of HIF-1 protein expression, changes in glucose metabolism and thereby response to radiotherapy treatment (18). PET imaging of hypoxia can be used to identify patients with hypoxic tumors who could benefit most from additional treatment, either by prescribing hypoxia-modifying drugs or by increasing the radiation dose to the tumor (19).Hypoxia-mediated resistance to chemotherapy treatmentHypoxia in solid tumors is associated with develop-ment of chemo-resistance. Majority of research focuses on the impact of hypoxia on apoptotic effect of cytotoxic medications, while minority refers to non-apoptotic path-ways of chemo-resistance in hypoxia (20). Multiple mech-anisms of hypoxia-mediated chemo-resistance are shown in MDA-MB 231 breast cancer cell line. Hypoxic precon-ditioning of these breast cancer cells results in resistance to multiple categories of chemotherapy medications: an-thracyclines, etoposide, mitoxantrone. Acute exposure to these medications results in multiple nuclear and cyto-plasmic changes (15).Cells with higher expression of HIF-1a have better ef-ficacy in double strand DNA repair, increased resistance to carboplatin, etoposide and ionizing radiation in com-parison HIF-1a deficient cells. Hypoxia can stimulate chemo-resistance to doxorubicin in experimental models of MCF-7 and HCC1973 cell lines. Likewise, that same resistance of the aforementioned cell lines can be amelio-rated through the addition of tanshinone IIA compound (Tan IIA). The assumed mechanism of Tan IIA effect is attributed to reduced expression of HIF-1a (12). In addi-tion to doxorubicin resistance, hypoxia contributes to enhanced epithelial-mesenchymal transition through modulated expression of E-cadherin and vimentin protein levels. Hypoxia reduces E-cadherin expression and in-creases vimentin expression. Tan IIA returns their expres-sion to a control level (12). These effects need to be con-firmed in additional in vivo research.Biological therapy in hypoxic microenvironmentFor long it was presumed that anti-angiogenic medica-tions have an important role in cancer management. Re-cent clinical studies question their effectiveness in breast cancer. Pre-clinical trials suggest that anti-angiogenic medications could even increase invasive and metastatic potential of breast cancer cells. Through stimulation of intra-tumor hypoxia in breast cancer xenografts, sunitinib and bevacizumab lead to proliferation of tumor stem cell population.Pre-clinical trials indicate that inhibitors of dichloro-acetate DCA and HIF inhibitors could enhance cur-rently limited efficacy of anti-VEGF antibody bevaci-zumab as angiogenesis inhibitor (21, 22).Melanomas that have the V600E BRAF mutation ex-hibit increased HIF-1a expression. Vemurafenib target-ing mutated BRAF was approved for the treatment of Natalija Dedić Plavetić et al. Hypoxia in solid tumors364 Period biol, Vol 116, No 4, 2014.advanced melanomas. Resistance to vemurafenib is being increasingly recognized. Vemurafenib-resistant melano-mas respond to treatment with an increase in HIF-1a levels, which thus serves as one of the mechanism of their resistance (23).CONCLUSIONHypoxic areas are present in many solid tumors due to inadequate blood supply and deranged vascular architec-tonics. 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Hypoxia in solid tumors: biological responses to hypoxia and implications on therapy and prognosis

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