Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide, and its incidence is increasing. Despite the significant improvement in management of HCC over the past 30 years, there are no effective chemoprevention strategies, and only one systemic therapy has been approved for patients with advanced tumors. This drug, sorafenib, acts on tumor cells and the stroma. HCC develops from chronically damaged tissue that contains large amounts of inflammation and fibrosis, which also promote tumor progression and resistance to therapy. Increasing our understanding of how stromal components interact with cancer cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets. Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide, and its incidence is increasing. Despite the significant improvement in management of HCC over the past 30 years, there are no effective chemoprevention strategies, and only one systemic therapy has been approved for patients with advanced tumors. This drug, sorafenib, acts on tumor cells and the stroma. HCC develops from chronically damaged tissue that contains large amounts of inflammation and fibrosis, which also promote tumor progression and resistance to therapy. Increasing our understanding of how stromal components interact with cancer cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets. Hepatocellular carcinoma (HCC) is the most common primary form of liver cancer and the third most deadly type of cancer globally, following lung and stomach cancers.1Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3641) Google Scholar With more than 750,000 new cases diagnosed every year worldwide, HCC is the sixth most common neoplasm.2Jemal A. Bray F. Center M.M. et al.Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (28937) Google Scholar Unlike other carcinomas, its incidence is steeply increasing, mainly due to the increasing prevalence of advanced hepatitis C virus (HCV) infection. HCC commonly arises in the setting of cirrhosis (>80% of cases), appearing 20 to 30 years after the initial insult to the liver. The use of antivirals and vaccination has successfully diminished the incidence of hepatitis B virus (HBV)-related HCC, although there are no effective chemopreventive strategies to attenuate the development of cancer once cirrhosis is established.3Villanueva A. Llovet J.M. Targeted therapies for hepatocellular carcinoma.Gastroenterology. 2011; 140: 1410-1426Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar HCC is diagnosed in most patients at advanced/symptomatic stages, when limited therapeutic options are available. The results of the randomized phase 3 SHARP (Sorafenib HCC Assessment Randomized Protocol) trial showed that the multikinase inhibitor sorafenib improved overall survival of patients with advanced HCC,4Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (7719) Google Scholar representing a breakthrough in the clinical management of this cancer. The liver tumor microenvironment is a complex mixture of tumoral cells within the extracellular matrix (ECM), combined with a complex mix of stromal cells and the proteins they secrete. Together, these elements contribute to the carcinogenic process. Cancer cells do not manifest the disease alone, and the stroma is inappropriately activated in cancer to contribute to malignant characteristics of tumor cells. The tumor microenvironment and the tumor cells create a complex cellular system with reciprocal signaling (Figure 1). Stromal components of the microenvironment can be divided into 3 subclasses: angiogenic cells, immune cells, and cancer-associated fibroblastic cells. There is growing evidence of the contribution of stromal cells to the hallmarks of cancer: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction.5Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (2328) Google Scholar Alterations within the microenvironment may favor tumor progression and play an importal role in chemoresistance.6Trimboli A.J. Cantemir-Stone C.Z. Li F. et al.Pten in stromal fibroblasts suppresses mammary epithelial tumours.Nature. 2009; 461: 1084-1091Crossref PubMed Scopus (397) Google Scholar, 7Bhowmick N.A. Chytil A. Plieth D. et al.TGF-beta signalling in fibroblasts modulates the oncogenic potential of adjacent epithelia.Science. 2004; 303: 848-851Crossref PubMed Scopus (0) Google Scholar Targeting stromal cells to abrogate their tumor-supporting role represents an attractive therapeutic strategy. The role of the microenvironment in tumor initiation and progression in HCC is critical. For instance, the status of nontumoral tissue has an important role in predicting tumor recurrence, which affects 70% of patients after resection or local ablation.8Llovet J.M. Schwartz M. Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma.Semin Liver Dis. 2005; 25: 181-200Crossref PubMed Scopus (703) Google Scholar Typically, there are 2 patterns of HCC recurrence: true metastasis of the primary tumor (generally within 2 years following resection/transplantation, defined as “early recurrence”) and de novo tumor (after 2 years from treatment or “late recurrence”).9Sherman M. Recurrence of hepatocellular carcinoma.N Engl J Med. 2008; 359: 2045-2047Crossref PubMed Scopus (142) Google Scholar, 10Hoshida Y. Villanueva A. Kobayashi M. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (947) Google Scholar Among these features, late recurrence is generally dictated by the persistence of protumorigenic signals within the damaged milieu of the fibrotic and cirrhotic liver11Tao Y. Ruan J. Yeh S.H. et al.Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data.Proc Natl Acad Sci U S A. 2011; 108: 12042-12047Crossref PubMed Scopus (106) Google Scholar; distinct molecular subgroups of HCC have been identified and linked to poor prognosis.12Chiang D.Y. Villanueva A. Hoshida Y. et al.Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.Cancer Res. 2008; 68: 6779-6788Crossref PubMed Scopus (409) Google Scholar, 13Boyault S. 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Toffanin S. et al.New strategies in hepatocellular carcinoma: genomic prognostic markers.Clin Cancer Res. 2010; 16: 4688-4694Crossref PubMed Scopus (98) Google Scholar In another context, the information encoded within the surrounding adjacent nontumoral tissue is essential to predicting the outcome of patients at very early stages (ie, tumors less than 2 cm without vascular invasion or extrahepatic spread) and may be even more relevant than the genomic profile of the tumor itself.10Hoshida Y. Villanueva A. Kobayashi M. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (947) Google Scholar These findings highlight the profound involvement of a dynamic network of nontumoral cells, molecules, and soluble factors in the generation of a supportive and permissive environment for initiation and progression of HCC. In this review, we provide an overview of current knowledge on the role of the tumor microenvironment in HCC and highlight potential prognostic and therapeutic implications. The development and progression of HCC is a multistage process. A chronic insult (eg, HCV, HBV, and alcohol) induces liver injury through reactive oxygen species (ROS) production, cellular DNA damage, endoplasmic reticulum stress, and necrosis of damaged hepatocytes. Most HCCs arise in the setting of chronic hepatitis induced by HCV or HBV infection. HCV is a single-stranded RNA virus that cannot integrate into the host genome but triggers an immune-mediated inflammatory response that promotes neoplastic transformation of damaged hepatocytes. Conversely, HBV can integrate into the genome of infected hepatocytes and promotes hepatocarcinogenesis through sustained inflammatory damage, hepatocyte regeneration, direct oncogenic transformation following integration of the viral genome into host genes, and the transactivating potential of several viral oncoproteins, especially HBx. The sustained dysregulation of the liver cell by HBV infection can ultimately affect DNA repair mechanisms and promote mutational events, which contribute to malignant transformation of hepatocytes. The hepatic response involves the activation of hepatic stellate cells and macrophages, which produce components of the ECM and growth factors that promote migration of endothelial cells, neoangiogenesis, and fibrosis. This process is associated with distortion of the parenchyma and vascular architecture characterized by progressive capillarization, with reduction of endothelial cell fenestrae size, and deposition of basement membrane components including collagen type IV and laminin within the space of Disse. This process, in the context of inflammation and oxidative DNA damage, favors the accumulation of mutations and epigenetic aberrations in preneoplastic hepatocytes or liver stem cells, thereby promoting the development of dysplastic nodules and their malignant transformation to early HCC.18Seitz H.K. Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress.Biol Chem. 2006; 387: 349-360Crossref PubMed Scopus (219) Google Scholar Therefore, HCC is not just a mixture of cells and ECM; it contains several cell types that interact with each other and the surrounding tissue, creating a complex interaction network within a permissive microenvironment. The stromal components support tumor growth and promote invasion through the stimulation of cancer cell proliferation, migration, and invasion and activation of angiogenesis, which together determine the phenotype of the tumor. The link between inflammation and generation of a preneoplastic milieu has been reported in many diseases, such as in the development of colorectal and pancreatic carcinomas in the context of inflammatory bowel disease and chronic pancreatitis, respectively.19Farrow B. Evers B.M. Inflammation and the development of pancreatic cancer.Surg Oncol. 2002; 10: 153-169Crossref PubMed Scopus (263) Google Scholar Once the cancer has been established, the contribution of the microenvironment to the regulation of tumor behavior has been well recognized for other malignancies, including breast, lung, and pancreatic carcinomas.5Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (2328) Google Scholar Abnormal ECM production and altered physical properties are frequently reported in malignancies. In breast carcinoma, for example, the tumor stroma is 10 times stiffer than in the normal breast, partially due to excess activity of lysyl oxidase and accumulation of collagen and other ECM components.20Lu P. Weaver V.M. Werb Z. The extracellular matrix: a dynamic niche in cancer progression.J Cell Biol. 2012; 196: 395-406Crossref PubMed Scopus (1786) Google Scholar Similarly, in pancreatic ductal adenocarcinoma, the large amounts of ECM proteins, activated fibroblasts, stellate cells, and inflammatory cells have been described as a “fortress-like” hypovascular barrier that impairs the delivery of chemotherapeutics and promotes aggressive neoplastic cell behavior.21Levental K.R. Yu H. Kass L. et al.Matrix crosslinking forces tumor progression by enhancing integrin signalling.Cell. 2009; 139: 891-906Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Different aspects of tumor biology, including development, progression, and response to therapy, can be affected by components of the tumor microenvironment. In mice, the recapitulation of human breast tumor orthotopic xenografts is largely determined by the presence of human tumor-derived stromal fibroblasts. Accordingly, studies in human tissues showed that tumor-associated fibroblasts (TAFs) isolated from breast carcinomas promoted the growth of breast cancer cells through the production of soluble factors such as colony-stimulating factor 1.22Orimo A. Gupta P.B. Sgroi D.C. et al.Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.Cell. 2005; 121: 335-348Abstract Full Text Full Text PDF PubMed Scopus (2665) Google Scholar In line with these findings, gene expression studies from the tumor microenvironment of human breast carcinomas reported up-regulation of several factors, including chemokines with protumorigenic function.23Allinen M. Beroukhim R. Cai L. et al.Molecular characterization of the tumor microenvironment in breast cancer.Cancer Cell. 2004; 6: 17-32Abstract Full Text Full Text PDF PubMed Scopus (975) Google Scholar The finding that the degree of activation of the stroma affects tumor growth and progression led to the concept of “stromal staging,” which has potential clinical utility. For example, increased production of ECM proteins including fibronectin, collagen IV, and tenascin C is associated with poor prognosis in patients with small cell lung carcinoma.24Sethi T. Rintoul R.C. Moore S.M. et al.Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo.Nat Med. 1999; 5: 662-668Crossref PubMed Scopus (523) Google Scholar This is related to the activation of prosurvival and antiapoptotic pathways in neoplastic cells following their adhesion to components of the ECM, for example, by the stimulation of the PI3K/Akt pathway downstream of β1 integrins.25Nicholson K.M. Anderson N.G. The protein kinase B/Akt signalling pathway in human malignancy.Cell Signal. 2002; 14: 381-395Crossref PubMed Scopus (1310) Google Scholar Furthermore, the abundance of specific stromal cells correlates with patient outcome. In breast cancer, the density of tumor-associated macrophages (TAMs) is associated with poor survival and reduced response to chemotherapy.26Denardo D.G. Brennan D.J. Rexhepaj E. et al.Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.Cancer Discov. 2011; 1: 54-67Crossref PubMed Scopus (531) Google Scholar Furthermore, recent findings indicate that the detection of p53 mutations in the stromal component increases the likelihood of nodal metastasis, suggesting that mutation-bearing stromal cells can provide a favorable setting for tumor spread.27Patocs A. Zhang L. Xu Y. et al.Breast-cancer stromal cells with TP53 mutations and nodal metastases.N Engl J Med. 2007; 357: 2543-2551Crossref PubMed Scopus (246) Google Scholar Interestingly, the stroma may also mediate resistance to molecular therapies by secreting growth factors (eg, hepatocyte growth factor [HGF]) that can stimulate survival responses and prevent apoptosis. This indicates that the tumor microenvironment actively favors the selection and expansion of cellular clones that are more likely to survive and adapt to the changes induced by stromal cells.28Yates L.R. Campbell P.J. Evolution of the cancer genome.Nat Rev Genet. 2012; 13: 795-806Crossref PubMed Scopus (371) Google Scholar Indeed, chemotherapy induces the production of colony-stimulating factor 1, a chemoattractant for macrophages, which exacerbates tumor progression by promoting angiogenesis, invasion, and metastasis of neoplastic cells.29Pollard J.W. Trophic macrophages in development and disease.Nat Rev Immunol. 2009; 9: 259-270Crossref PubMed Scopus (778) Google Scholar In one study, the pharmacologic blockade of macrophage recruitment markedly improved the ability of the chemotherapeutic agent paclitaxel to slow the growth of both primary and metastatic tumors.26Denardo D.G. Brennan D.J. Rexhepaj E. et al.Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.Cancer Discov. 2011; 1: 54-67Crossref PubMed Scopus (531) Google Scholar Finally, a stromal gene signature predicts resistance to neoadjuvant chemotherapy in patients with estrogen receptor–negative breast cancer.30Farmer P. Bonnefoi H. Anderle P. et al.A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.Nat Med. 2009; 15: 68-74Crossref PubMed Scopus (450) Google Scholar The precancerous milieu of chronic liver disease is characterized by neoangiogenesis, including several vascular abnormalities such as arterialization and sinusoidal capillarization, as well as inflammation and fibrosis. These biological processes become more pronounced with progression of liver failure, in which the incidence of cancer increases exponentially (Figure 2). Synchronous events occurring in this setting also include hypoxia, oxidative stress, and autophagy. Angiogenesis plays an important role in hepatocarcinogenesis from its early stages.31Zhu A.X. Duda D.G. Sahani D.V. et al.HCC and angiogenesis: possible targets and future directions.Nat Rev Clin Oncol. 2011; 8: 292-301Crossref PubMed Scopus (348) Google Scholar HCC is a highly vascularized tumor; indeed, pathological angiogenesis is one of the main contributors to chronic liver diseases. The hepatic wound-healing response due to chronic liver injury leads to fibrogenesis, a process that entails secretion of several proangiogenic factors by the stromal cells, especially matrix metalloproteinases (MMPs), platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β1, fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF). Moreover, ECM deposition and anatomic alterations during the fibrogenic process provoke resistance to blood flow that reduces metabolic exchange of oxygen, favoring hypoxia. Indeed, gene expression of VEGF, the most critical proangiogenic factor, is already induced in dysplastic nodules and further increases according to the progression of HCC development.31Zhu A.X. Duda D.G. Sahani D.V. et al.HCC and angiogenesis: possible targets and future directions.Nat Rev Clin Oncol. 2011; 8: 292-301Crossref PubMed Scopus (348) Google Scholar Once the tumor is established, the survival of neoplastic cells requires the formation of a new vascular network to provide nutrients and oxygen. The angiogenic process in HCC is complex and tightly regulated, resulting from the balance between multiple angiogenic and antiangiogenic factors from the tumor and the host cells. Growth of the tumor mass creates a nutrient- and oxygen-deprived environment, which induces the activation and proliferation of endothelial cells (ECs) to sprout new vessels from preexisting ones.32North S. Moenner M. Bikfalvi A. Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors.Cancer Lett. 2005; 218: 1-14Crossref PubMed Scopus (113) Google Scholar ECs become proliferative and liberate enzymes to disrupt the basement membrane, and they eventually migrate to their final location where they assemble to form a new vessel together with the ECM.33Coulon S. Heindryckx F. Geerts A. et al.Angiogenesis in chronic liver disease and its complications.Liver Int. 2011; 31: 146-162Crossref PubMed Scopus (186) Google Scholar The expression of VEGF correlates with the aggressiveness of HCC.31Zhu A.X. Duda D.G. Sahani D.V. et al.HCC and angiogenesis: possible targets and future directions.Nat Rev Clin Oncol. 2011; 8: 292-301Crossref PubMed Scopus (348) Google Scholar The effects of VEGF are transduced following binding to its receptors, VEGFR1 and VEGFR2, to activate several signaling pathways involved in proliferation, migration, and invasion of ECs.34Liu Y. Poon R.T. Li Q. et al.Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584.Cancer Res. 2005; 65: 3691-3699Crossref PubMed Scopus (96) Google Scholar In addition, VEGF can function as a cytokine that directly affects hepatic stellate cells, Kupffer cells, and hepatocytes35LeCouter J. Moritz D.R. Li B. et al.Angiogenesis-independent endothelial protection of liver: role of VEGFR-1.Science. 2003; 299: 890-893Crossref PubMed Scopus (537) Google Scholar, 36Lichtenberger B.M. Tan P.K. Niederleithner H. et al.Autocrine VEGF signalling synergizes with EGFR in tumor cells to promote epithelial cancer development.Cell. 2010; 140: 268-279Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and mediates the dissolution of the vascular basement membrane and the interstitial matrix.31Zhu A.X. Duda D.G. Sahani D.V. et al.HCC and angiogenesis: possible targets and future directions.Nat Rev Clin Oncol. 2011; 8: 292-301Crossref PubMed Scopus (348) Google Scholar VEGF and angiopoietin 2 plasma levels have been identified as independent prognostic biomarkers in patients with advanced HCC.37Llovet J.M. Pena C.E. Lathia C.D. et al.Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma.Clin Cancer Res. 2012; 18: 2290-2300Crossref PubMed Scopus (381) Google Scholar Angiopoietin 2 is frequently up-regulated in HCC and boosts the effect of VEGF on ECs.38Yoshiji H. Kuriyama S. Noguchi R. et al.Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice.Gut. 2005; 54: 1768-1775Crossref PubMed Scopus (0) Google Scholar Moreover, the Tie-2 receptor is expressed by both ECs and stellate cells, further emphasizing the complex orchestration of angiogenic regulation in liver tumors. FGF is a member of the heparin-binding growth factors and acts synergistically with VEGF to induce angiogenesis, whereas PDGF is involved in cell migration and new vessel maturation. Cancer cells secrete PDGF, which acts through a paracrine mechanism that involves other cell types such as ECs and fibroblasts and correlates with cancer progression.39Bronzert D.A. Pantazis P. Antoniades H.N. et al.Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines.Proc Natl Acad Sci U S A. 1987; 84: 5763-5767Crossref PubMed Google Scholar Other significant mediators in tumor neoangiogenesis are integrins and cadherins, which mediate cell-matrix and cell-cell interactions, respectively, to establish contacts required for new vascular tube formation.33Coulon S. Heindryckx F. Geerts A. et al.Angiogenesis in chronic liver disease and its complications.Liver Int. 2011; 31: 146-162Crossref PubMed Scopus (186) Google Scholar HCCs arises in a diseased liver with a dynamic inflammatory environment that predisposes to initiation of cancer. Inflammation, an essential part of the wound-healing response of the liver and undoubtedly beneficial in the short-term, perpetuates chronic injury. Chronic inflammation drives a maladaptive reparative reaction and stimulates liver cell death and regeneration, which is eventually associated with the development of dysplastic nodules and cancer (Figure 3). Several inflammatory mediators have been implicated in sustained inflammation and immunosuppression associated with development of HCC. Carcinogenesis is associated with persistent cytokine production that can stimulate many liver cell types with a variety of unique as well as redundant interactions. Altered cytokine profiles have been described in HCC not only in tumor cells but also in the surrounding tissue; however, the full portrait of their mechanistic role remains unclear. A predominant role of the Th2-like (interleukin [IL]-4, IL-8, IL-10, and IL-5) cytokine compared with Th1-like (IL-1α, IL-1β, IL-2, tumor necrosis factor α) cytokine in the microenvironment has been associated with a more aggressive and metastatic HCC phenotype.40Budhu A. Wang X.W. The role of cytokines in hepatocellular carcinoma.J Leukoc Biol. 2006; 80: 1197-1213Crossref PubMed Scopus (0) Google Scholar, 41Budhu A. Forgues M. Ye Q.H. et al.Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment.Cancer Cell. 2006; 10: 99-111Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar IL-6 is an abundant cytokine in cirrhotic livers, produced by Kupffer cells in response to hepatocyte damage, and a potent activator of STAT3, and elevated levels in serum are associated with risk of HCC and poor prognosis.10Hoshida Y. Villanueva A. Kobayashi M. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (947) Google Scholar, 42Tilg H. Wilmer A. 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Higher levels of IL-2 and IL-15 in peritumoral liver tissue are also associated with a decreased rate of intrahepatic tumor recurrence and prolonged overall survival.47Zhou H. Huang H. Shi J. et al.Prognostic value of interleukin 2 and interleukin 15 in peritumoral hepatic tissues for patients with hepatitis B-related hepatocellular carcinoma after curative resection.Gut. 2010; 59: 1699-1708Crossref PubMed Scopus (0) Google Scholar Chemokines (eg, CXCL12, CX3CL1, CCL20) are cytokine-like molecules with chemotactic properties critical to cell trafficking into and out of the tumor microenvironment. They orchestrate the inflammatory response through their binding to 4 families of receptors (CCR, CXCR, CX3CR, and XCR) found mainly in inflammatory, endothelial, and epithelial cells. Chemokines have been implicated in many key steps of cancer development, including evasion of the immune system, angiogenesis, invasion, and dissemination.48Roussos E.T. Condeelis J.S. Patsialou A. Chemotaxis in cancer.Nat Rev Cancer. 2011; 11: 573-587Crossref PubMed Scopus (552) Google Scholar The CXCL12-CXCR4 axis is especially important in regulation of angiogenesis and is highly expressed in HCC compared with cirrhosis.49Li W. Gomez E. Zhang Z. Immunohistochemical expression of stromal cell-derived factor-1 (SDF-1) and CXCR4 ligand receptor system in hepatocellular carcinoma.J Exp Clin Cancer Res. 2007; 26: 527-533PubMed Google Scholar CXCL12 binds CXCR4 in endothelial cells and promotes migration, proliferation, and development of new vessels, acting synergistically with VEGF.50Kryczek I. Lange A. Mottram P. et al.CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers.Cancer Res. 2005; 65: 465-472PubMed Google Scho