Abstract
Metastasis remains the leading cause of cancer-related deaths. To date, there are no specific treatments targeting disseminated disease. New therapeutic options will become available only if we enhance our understanding of mechanisms underlying metastatic spread. A large body of literature shows that the metastatic potential of tumor cells is strongly influenced by microenvironmental cues such as low oxygen (hypoxia). Clinically, hypoxia is a hallmark of most solid tumors and is associated with increased metastasis and poor survival in a variety of cancer types. Mechanistically, hypoxia influences multiple steps within the metastatic cascade and particularly impacts the interactions between tumor cells and host stroma at both primary and secondary sites. Here we review current evidence for a hypoxia-induced tumor secretome and its impact on metastatic progression. These studies have identified potential biomarkers and therapeutic targets that could be integrated into strategies for preventing and treating metastatic disease.
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References
Tjalsma H, Bolhuis A, Jongbloed JD, Bron S, van Dijl JM (2000) Signal peptide-dependent protein transport in Bacillus subtilis: a genome-based survey of the secretome. Microbiol Mol Biol Rev 64:515–547
Chenau J, Michelland S, Seve M (2008) Le sécrétome: définitions et intérêt biomédical. La Revue de Médecine Interne 29:606–608
Palade G (1975) Intracellular aspects of the process of protein synthesis. Science 189:867–867
Ferro-Novick S, Brose N (2013) Traffic control system within cells. Nature 504:98–98
Cocucci E, Meldolesi J (2015) Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol 25:364–372
Vlassov AV, Magdaleno S, Setterquist R, Conrad R (2012) Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 1820:940–948
Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19:43–51
Dong H et al (2016) Breast Cancer MDA-MB-231 cells use secreted heat shock protein-90alpha (Hsp90α) to survive a hostile hypoxic environment. Sci Rep 6:20605
Ehrenfried JA, Herron BE, Townsend CM, Evers BM (1995) Heat shock proteins are differentially expressed in human gastrointestinal cancers. Surg Oncol 4:197–203
Li CF et al (2008) Heat shock protein 90 overexpression independently predicts inferior disease-free survival with differential expression of the and isoforms in gastrointestinal stromal tumors. Clin Cancer Res 14:7822–7831
Gress TM et al (1994) Differential expression of heat shock proteins in pancreatic carcinoma. Cancer Res 54:547–551
Bao S et al (2004) Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell 5:329–339
Song G et al (2009) Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt-mediated HIF-1alpha up-regulation and MMP9 activation. J Cell Mol Med 13:1706–1718
Song G et al (2008) Osteopontin promotes ovarian cancer progression and cell survival and increases HIF-1alpha expression through the PI3-K/Akt pathway. Cancer Sci 99:1901–1907
Xue M et al (2017) Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer 16:143
Panigrahi GK et al (2018) Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells. Sci Rep 8:290
Adair TH, Montani J-P (2010) Angiogenesis. In: Colloquium series on integrated systems physiology: from molecule to function, vol. 2, pp 1–84
Krock BL, Skuli N, Simon MC (2012) Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2:1117–1133
Li B et al (2006) VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J 20:1495–1497
Compernolle V et al (2002) Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8:702–710
Rankin EB et al (2008) Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 27:5354–5358
Liu Y, Cox SR, Morita T, Kourembanas S (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res 77:638–643
Levy AP, Levy NS, Wegner S, Goldberg MA (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333–13340
Ceradini DJ et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864
Reynolds LP, Redmer DA (1998) Expression of the angiogenic factors, basic fibroblast growth factor and vascular endothelial growth factor, in the ovary. J Anim Sci 76:1671
Hong KH (2005) Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood 105:1405–1407
Matsui J, Wakabayashi T, Asada M, Yoshimatsu K, Okada M (2004) Stem cell factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial cells. J Biol Chem 279:18600–18607
Han ZB et al (2008) Hypoxia-inducible factor (HIF)-1 directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF). Carcinogenesis 29:1853–1861
Sun L et al (2006) Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9:287–300
Litz J (2006) Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1 activity and vascular endothelial growth factor expression in small cell lung cancer cells. Mol Cancer Ther 5:1415–1422
Hellstrom M, Kalen M, Lindahl P et al (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055
Iivanainen E, Nelimarkka L, Elenius V et al (2003) Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J 17:1609–1621
Murakami M (2012) Signaling required for blood vessel maintenance: molecular basis and pathological manifestations. Int J Vasc Med 2012:293641
Laderoute KR et al (2000) Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor. Clin Cancer Res 6:2941–2950
Umezu T et al (2014) Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood 124:3748–3757
Hsu Y-L et al (2017) Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene 36:4929–4942
Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH (2013) Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem 288:34343–34351
Mao G et al (2015) Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer. Angiogenesis 18:373–382
Wang R et al (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468:829–833
Ricci-Vitiani L et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828
Soda Y et al (2011) Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci USA 108:4274–4280
Chen H-F et al (2014) Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis. Nat Commun 5:4697
Du R et al (2008) HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220
Lin S et al (2012) Chemokine C-C motif receptor 5 and C-C motif ligand 5 promote cancer cell migration under hypoxia. Cancer Sci 103:904–912
Leek RD et al (2000) Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol 190:430–436
Grimshaw MJ, Wilson JL, Balkwill FR (2002) Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors. Eur J Immunol 32:2393–2400
Grimshaw MJ (2007) Endothelins and hypoxia-inducible factor in cancer. Endocr Relat Cancer 14:233–244
Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952
Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI (2004) Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172:989–999
Mantovani A (2010) The growing diversity and spectrum of action of myeloid-derived suppressor cells. Eur J Immunol 40:3317–3320
Fridman WH et al (2011) Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res 71:5601–5605
Facciabene A et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475:226–230
Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 13:5262–5270
Hao N-B et al (2012) Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol 2012:948098–948011
Gabrilovich DI et al (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103
Curiel TJ et al (2003) Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity. Nat Med 9:562–567
Whiteside TL, Mandapathil M, Schuler P (2011) The role of the adenosinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem 18:5217–5223
Yang L et al (2003) Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J Clin Investig 111:727–735
Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68:5439–5449
Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67:4507–4513
Barsoum IB et al (2011) Hypoxia induces escape from innate immunity in Cancer cells via increased expression of ADAM10: role of nitric oxide. Cancer Res 71:7433–7441
Chen X et al (2017) Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep 38:522–528
Wang X et al (2018) Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis. Cancer Res 78(16):4586–4598. https://doi.org/10.1158/0008-5472.CAN-17-3841
Berchem G et al (2016) Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer. Oncoimmunology 5:e1062968
Ye S-B et al (2016) Exosomal miR-24-3p impedes T-cell function by targeting FGF11and serves as a potential prognostic biomarker for nasopharyngeal carcinoma. J Pathol 240:329–340
Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374
Sudhan DR, Siemann DW (2013) Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells. Clin Exp Metastasis 30:891–902
Krishnamachary B et al (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63:1138–1143
Erler JT et al (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44
Chen Y et al (2016) Lysyl hydroxylase 2 is secreted by tumor cells and can modify collagen in the extracellular space. J Biol Chem 291:25799–25808
Eisinger-Mathason TSK et al (2013) Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov 3:1190–1205
Gilkes DM et al (2013) Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis. Mol Cancer Res 11:456–466
Chaturvedi P, Gilkes DM, Takano N, Semenza GL (2014) Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. Proc Natl Acad Sci 111:E2120–E2129
Chaturvedi P et al (2013) Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest 123:189–205
Haemmerle M et al (2016) FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal. J Clin Invest 126:1885–1896
Díaz B, Yuen A, Iizuka S, Higashiyama S, Courtneidge SA (2013) Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol 201:279–292
Ramteke A et al (2015) Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog 54:554–565
Li L et al (2016) Exosomes derived from hypoxic Oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a Prometastatic phenotype. Cancer Res 76:1770–1780
Fidler IJ (1970) Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst 45:773–782
Zucchella M et al (1989) Human tumor cells cultured ‘in vitro’ activate platelet function by producing ADP or thrombin. Haematologica 74:541–545
Bastida E, Ordinas A, Giardina SL, Jamieson GA (1982) Differentiation of platelet-aggregating effects of human tumor cell lines based on inhibition studies with apyrase, hirudin, and phospholipase. Cancer Res 42:4348–4352
Pinto S et al (1993) Increased thromboxane A2 production at primary tumor site in metastasizing squamous cell carcinoma of the larynx. Prostaglandins Leukot Essent Fatty Acids 49:527–530
Monteiro RQ et al (2016) Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model. Oncol Lett 12:315–322
Gong L, Cai Y, Zhou X, Yang H (2012) Activated platelets interact with lung cancer cells through P-selectin glycoprotein ligand-1. Pathol Oncol Res 18:989–996
Nieswandt B, Hafner M, Echtenacher B, Männel DN (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59:1295–1300
Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11:123–134
Palumbo JS, Degen JL (2007) Mechanisms linking tumor cell-associated procoagulant function to tumor metastasis. Thromb Res 120(Suppl 2):S22–S28
Kopp H-G, Placke T, Salih HR (2009) Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res 69:7775–7783
Labelle M, Hynes RO (2012) The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during Hematogenous dissemination. Cancer Discov 2:1091–1099
Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12:265–277
Placke T et al (2012) Platelet-derived MHC class I confers a Pseudonormal phenotype to Cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res 72:440–448
Granot Z et al (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20:300–314
Reymond N, d'Água BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870
Zhang H et al (2011) HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 31:1757–1770
Gupta GP et al (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446:765–770
Wolf MJ et al (2012) Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell 22:91–105
Weis S, Cui J, Barnes L, Cheresh D (2004) Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol 167:223–229
Huang Y et al (2009) Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res 69:7529–7537
Schumacher D, Strilic B, Sivaraj KK, Wettschureck N, Offermanns S (2013) Platelet-derived nucleotides promote tumor-cell Transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24:130–137
Lee E et al (2014) Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis. Nat Commun 5:112
Cox TR et al (2015) The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522:106–110
Wong CCL et al (2014) Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma. Hepatology 60:1645–1658
Manisterski M, Golan M, Amir S, Weisman Y, Mabjeesh N (2014) Hypoxia induces PTHrP gene transcription in human cancer cells through the HIF-2α. Cell Cycle 9:3747–3753
Guise TA et al (1996) Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Investig 98:1544–1549
Mazzieri R et al (2011) Targeting the ANG2/TIE2 Axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19:512–526
Oskarsson T et al (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17:867–874
Loo JM et al (2015) Extracellular metabolic energetics can promote cancer progression. Cell 160:393–406
Rankin EB, Giaccia AJ (2016) Hypoxic control of metastasis. Science 352:175–180
Acknowledgments
This work was supported by NIH Grant 1U54CA210173-01. We apologize to other researchers whose work we could not cite owing to space constraints.
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Liu, Y., Ciotti, G.E., Eisinger-Mathason, T.S.K. (2019). Hypoxia and the Tumor Secretome. In: Gilkes, D. (eds) Hypoxia and Cancer Metastasis. Advances in Experimental Medicine and Biology, vol 1136. Springer, Cham. https://doi.org/10.1007/978-3-030-12734-3_4
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