PHYSIOLOGICAL SYSTEM OF CONJUNCTIVE TISSUE AND ONCOGENESIS. II. EXTRACELLULAR MATRIX AND METASTASIS
Keywords:
malignant tumors, metastasis, extracellular matrix, epithelial-mesenchymal transition, metastatic niche, hypoxia, the cells of the immune system, angiogenesis.Abstract
Summary. The review presents contemporary information on the role of the extracellular component of the extracellular matrix (ECM) of the connective tissue system
in the pathogenesis of metastasis. After a brief presentation of the general ideas about the ECM, focusing mainly on the work of the last decade, the following topics are
discusses: the state of ECM in hypoxic conditions; the involvement of ECM components in the formation of metastatic niches; possible ways of influence of ECM on epithelial-mesenchymal transition; the nature of the interaction of ECM components with cells of the immune system;
the role of the ECM in angiogenesis. The presented information lead to the conclusion that the ECM carries out
control of invasion and metastasis of tumor cells; its dysregulation is a key step in the metastatic process. Current
knowledge allows us to consider changes of ECM, an essential step in the pathogenesis of the neoplastic process
and its components as a target for possible therapeutic effect, taking into account their role in the development of
various tumors.
References
Fidler IJ. The pathogenesis of cancer metastasis: the «seed and soil» hypothesis revisited. Nat Rev Cancer 2003; 3: 453–8.
Malik R, Lelkes PI, Cukierman E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol 2015; 33: 230–6.
Cox TR, Rumney RM, Schoof EM, at al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 2015; 522: 106–10.
Venning FA, Wullkopf L, Erler JT. Targeting ECM disrupts cancer progression. Front Oncol 2015; 5: 224.
Fidler IJ. The biology of brain metastasis: challenges for therapy. Cancer J 2015; 21: 284–93.
Fidler IJ. Commentary on «Tumor Heterogeneity and the Biology of Cancer Invasion and Metastasis». Cancer Res 2016; 76: 3441–2.
Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989; 8 (2): 98–101.
Fidler IJ. The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 2011; 21: 107–12.
Langley RR, Fidler IJ. The biology of brain metastasis.Clin Chem 2013; 59: 180–9.
Langley RR, Fidler IJ. The seed and soil hypothesis revisitedthe role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 2011; 128: 2527–35.
Özdemir B, Hensel J, Secondini C, et al. The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches. PLoS One 2014; 9: e114530.
Malik R, Lelkes PI, Cukierman E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol 2015; 33: 230–6.
Kovács KA, Hegedus B, Kenessey I, et al. Tumor type-specific and skin region-selective metastasis of human cancers: another example of the «seed and soil» hypothesis. Cancer Metastasis Rev 2013; 32: 493–9.
López-Ceballos P, Herrera-Reyes AD, Coombs D, et al. In vivo regulation of integrin turnover by outside-in activation. J Cell Sci 2016; 129: 2912–24.
Xiong J, Balcioglu HE, Danen EH. Integrin signaling in control of tumor growth and progression. Int J Biochem Cell Biol 2013; 45: 1012–5.
Goel HL, Pursell B, Standley C, et al. Neuropilin-2 regulates α6β1 integrin in the formation of focal adhesions and signaling. J Cell Sci 2012; 125: 497–506.
Fujimaki T, Price JE, Fan D, et al. Selective growth of human melanoma cells in the brain parenchyma of nude mice. Melanoma Res 1996; 6: 363–71.
Fidler IJ, Schackert G, Zhang RD, et al. The biology of melanoma brain metastasis. Cancer Metastasis Rev 1999; 18: 387–400.
Cox TR,Erler JT. Molecular pathways: connecting fibrosis and solid tumor metastasis. Clin Cancer Res 2014; 20: 3637–43.
Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2014; 15: 786–801.
Hynes RO, Naba A. Overview of the matrisome — an inventory of extracellular matrix constituents and functions. Cold Spring Harb Perspect Biol 2012; 4: a004903.
Nikitovic D, Corsini E, Kouretas D, et al. ROS-major mediators of extracellular matrix remodeling during tumor progression. Food Chem Toxicol 2013; 61: 178–86.
Lu P,WeaverVM,Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012; 196: 395–406.
Miles FL, Sikes RA. Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res 2014; 12: 297–312.
Levental KR, Yu H, Kass L, Lakins JN, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009; 139: 891–906.
Theocharis AD, Skandalis SS, Gialeli C, et al. Extracellular matrix structure. Adv Drug Deliv Rev 2016; 97: 4–27.
Bai C, Yang M, Fan Z, et al. Associations of chemo- and radio-resistant phenotypes with the gap junction, adhesion and extracellular matrix in a three-dimensional culture model of soft sarcoma. J Exp Clin Cancer Res 2015; 34: 58.
Multhaupt HA, Leitinger B, Gullberg D, et al. Extracellular matrix component signaling in cancer. Adv Drug Deliv Rev 2016; 97: 28–40.
Seguin L, Desgrosellier JS, Weis SM, et al. Cheresh Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 2015; 25: 234–40.
Rodriguez A, Karen J, Gardner H, et al. Integrin alpha1beta1 is involved in the differentiation into myofibroblasts in adult reactive tissues in vivo. J Cell Mol Med 2009; 13: 3449–62.
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141: 52–67.
Kim GE, Lee JS, Choi YD, et al. Expression of matrix metalloproteinases and their inhibitors in different immunohistochemicalbased molecular subtypes of breast cancer. BMC Cancer 2014; 14: 959.
Bodnar M, Szylberg L, Kazmierczak W, et al. Differentiated expression of membrane type metalloproteinases (MMP-14, MMP-15) and pro-MMP2 in laryngeal squamous cell carcinoma. A novel mechanism. J Oral Pathol Med 2013; 42: 267–74.
Vosseler S, Lederle W, Airola K, et al.Distinct progression-associated expression of tumor and stromal MMPs in HaCaT skin SCCs correlates with onset of invasion. Int J Cancer 2009; 125: 2296–306.
Huang Y, Yu H, Lei H, et al. Matrix metalloproteinase 7 is a useful marker for 5-fluorouracil-based adjuvant chemotherapy in stage II and stage III colorectal cancer patients. Med Oncol 2014; 31: 824.
Wang WS, Chen PM, Wang HS, et al. Matrix metalloproteinase-7 increases resistance to Fas-mediated apoptosis and is a poor prognostic factor of patients with colorectal carcinoma. Carcinogenesis 2006; 27: 1113–20.
Бережная НМ. Семейства интерлейкинов: биология ионкогенез. Киев: Наукова думка, 2013. 575 с.
Ogden SR, Noto JM, Allen SS, et al. Matrix metalloproteinase-7 and premalignant host responses in Helicobacter pylori-infected mice. Cancer Res 2010; 70: 30–5.
Dayer C, Stamenkovic I. Recruitment of matrix metalloproteinase-9 (MMP-9) to the fibroblast cell surface by lysyl hydroxylase 3 (LH3) triggers transforming growth factor-β (TGF-β) activation and fibroblast differentiation. J Biol Chem 2015; 290: 13763–78.
Nakamura T, Kuwai T, Kim JS, et al. Stromal metalloproteinase-9 is essential to angiogenesis and progressive growth of orthotopic human pancreatic cancer in parabiont nude mice. Neoplasia 2007; 9: 979–86.
Xue Z,Wu X,Chen X, et al. MT3-MMP down-regulation promotes tumorigenesis and correlates to poor prognosis in esophageal squamous cell carcinoma. Cancer Med 2016. doi: 10.1002/cam4.790. [Epub ahead of print].
Morell-Quadreny L, Rubio J, Lopez-Guerrero JA, et al. Disruption of basement membrane, extracellular matrix metalloproteinases and E-cadherin in renal-cell carcinoma. Anticancer Res 2003; 23: 5005–10.
Musumeci G, Magro G, Cardile V, et al. Characterization of matrix metalloproteinase-2 and -9, ADAM-10 and N-cadherin expression in human glioblastoma multiforme. Cell Tissue Res 2015; 362: 45–60.
Foda AA, El-Hawary AK, Aziz AA. Colorectal adenocarcinoma with mucinous component: relation of MMP-13, EGFR, and Ecadherin expressions to clinicopathological features and prognosis. APMIS 2015; 123: 502–8.
Bourguignon LY, Wong G, Earle CA, et al. Interaction of low molecular weight hyaluronan with CD44 and toll-like receptors promotes the actin filament-associated protein 110-actin binding and MyD88-NFκB signaling leading to proinflammatory cytokine/chemokine production and breast tumor invasion. Cytoskeleton (Hoboken) 2011; 68 (12): 671–93.
Heo JH, Song JY, Jeong JY, et al. Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer. J Clin Pathol 2016; 69 (2): 109–16.
Lowy CM,OskarssonT. TenascinC in metastasis: a view from the invasive front. Cell Adh Migr 2015; 9: 112–24.
Bedore J, Leask A, Séguin CA. Targeting the extracellular matrix: matricellular proteins regulate cell-extracellular matrix communication within distinct niches of the intervertebral disc. Matrix Biol 2014; 37: 124–30.
Barney LE, Dandley EC, Jansen LE, et al. A cell-ECM screening method to predict breast cancer metastasis. Integr Biol (Camb) 2015; 7: 198–212.
Tung JC, Barnes JM, Desai SR, et al. Tumor mechanics and metabolic dysfunction. Free Radic Biol Med 2015; 79: 269–80.
Naba A, Clauser KR, Lamar JM, et al.Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. Elife 2014; 3: e01308.
Naba A, Clauser KR, Whittaker CA, et al.Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver. BMC Cancer 2014; 14: 518.
Zhu J, Liang L, Jiao Y, et al. Enhanced invasion of metastatic cancer cells via extracellular matrix interface. China Physical Sciences-Oncology Alliance. PLoS One 2015; 10: e0118058.
Wirtz D,Konstantopoulos K,Searson PC. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat Rev Cancer 2011; 11: 512–22.
van Kempen LC, Rhee JS, Dehne K, et al. Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment. Differentiation 2002; 70: 610–23.
Faurobert E, Bouin AP, Albiges-Rizo C. Microenvironment, tumor cell plasticity, and cancer. Curr Opin Oncol 2015;
: 64–70.
Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast 2013; 22: S66–72.
Insua-Rodríguez J, Oskarsson T. The extracellular matrix in breast cancer. Adv Drug Deliv Rev 2016; 97: 41–55.
Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 2010; 86: 236–42.
Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 2013; 123: 3664–71.
Hanna SC, Krishnan B, Bailey ST, et al. HIF1α and HIF2α independently activate SRC to promote melanoma metastases. J Clin Invest 2013; 123: 2078–93.
Gilkes DM, Bajpai S, Chaturvedi P, et al. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem 2013; 288: 10819–29.
Catalano V, Turdo A, Di Franco S, et al. Tumor and its microenvironment: a synergistic interplay. Semin Cancer Biol 2013; 23: 522–32.
Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer 2014; 14: 430–9.
Lopez JI, Kang I, You WK, et al. In situ force mapping of mammary gland transformation. Integr Biol 2011: 3 (9): 910–21.
Chang YN, Zhang K, Hu ZM, et al. Hypoxia-regulated lncRNAs in cancer. Gene 2016; 575: 1–8.
Semenza GL. The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta 2016; 1863: 382–91.
Semenza GL, Ruvolo PP. Introduction to tumor microenvironment regulation of cancer cell survival, metastasis, inflammation, and immune surveillance. Biochim Biophys Acta 2016; 1863: 379–81.
Mao Y, Keller ET, Garfield DH, et al. Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 2013; 32: 303–15.
Rong L, Li R, Li S, et al. Immunosuppression of breast cancer cells mediated by transforming growth factor-β in exosomes from cancer cells. Oncol Lett 2016; 11: 500–4.
Cui W, Zhou J, Dehne N, et al. Hypoxia induces calpain activity and degrades SMAD2 to attenuate TGFβ signaling in macrophages. Cell Biosci 2015; 5: 36.
Lee SL,Ryu H,Son AR, et al.TGF-β and hypoxia/reoxygenation promoteradioresistanceof A549 lung cancer cells through activation of Nrf2 and EGFR. Oxid Med Cell Longev 2016; 2016: 6823471.
Iwadate Y, Matsutani T, Hirono S, et al. Transforming growth factor-β and stem cell markers are highly expressed around necrotic areas in glioblastoma. J Neurooncol 2016; 18 [Epub ahead of print].
Wynn TA,Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 2010; 30: 245–57.
Erler JT, Weaver VM. Three-dimensional context regulation of metastasis. Clin Exp Metastasis 2009; 26: 35–49.
Descot A, Oskarsson T. The molecular composition of the metastatic niche. Exp Cell Res 2013; 319: 1679–86.
Santamaria-Martínez A, Huelsken J. The niche under siege: novel targets for metastasis therapy. J Intern Med 2013; 274: 127–36.
Sleeman JP. The metastatic niche and stromal progression. Cancer Metastasis Rev 2012; 31: 429–40.
Lowy CM,Oskarsson T. Tenascin C in metastasis: A view from the invasive front. Cell Adh Migr 2015; 9: 112–24.
Oskarsson T, Acharyya S, Zhang XH, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 2011; 17: 867–74.
Huang CP, Lu J, Seon H, et al. Engineering microscale cellular niches for three-dimensional multicellular co-cultures. Lab Chip 2009; 9: 1740–8.
Chiovaro F,Martina E,Bottos A, et al. Transcriptional regulation oftenascin-Wby TGF-beta signaling in the bone metastatic niche of breast cancer cells. Int J Cancer 2015; 137: 1842–54.
Wang Z, Xiong S, Mao Y, et al. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis. J Pathol 2016 [Epub ahead of print].
Ratajczak-Wielgomas K, Dziegiel P. The role of periostin in neoplastic processes. Folia Histochem Cytobiol 2015; 53: 120–32.
Kii I,Nishiyama T,Li M, et al. Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. J Biol Chem 2010; 285: 2028–39.
Oskarsson T, Massagué J. Extracellular matrix players in metastatic niches. EMBO J 2012; 31: 254–6.
Eyles J, Puaux AL, Wang X, et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest 2010; 120: 2030–9.
Wong CC,Gilkes DM,Zhang H, et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci U S A 2011; 108: 16369–74.
Pietilä M, Ivaska J, Mani SA. Whom to blame for metastasis, the epithelial-mesenchymal transition or the tumor microenvironment? Cancer Lett 2016; 380: 359–68.
Kalluri R,Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112: 1776–84.
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420–8.
Yang J, Zhang X, Zhang Y, et al. HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J Exp Clin Cancer Res 2016; 35: 26.
Ungewiss C, Rizvi ZH, Roybal JD, et al. The microRNA-200/Zeb1 axis regulates ECM-dependent β1-integrin/FAK
signaling, cancer cell invasion and metastasis through CRKL. Sci Rep 2016; 6: 18652.
Zong W, Yu C, Wang P, et al. Overexpression of SASH1 inhibits TGF-β1-Induced EMT in gastric cancer cells. Oncol Res 2016; 24: 17–23.
AbulaitiA,Shintani Y,Funaki S, et al. Interaction between nonsmall-cell lung cancer cells and fibroblasts via enhancement of TGF-β signaling by IL-6. Lung Cancer 2013; 82: 204–13.
Fuxe J, Karlsson MC. TGF-β-induced epithelial-mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol 2012; 22: 455–61.
Su S, Liu Q, Chen J, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 2014; 25: 605–20.
Bonde AK, Tischler V, Kumar S, et al. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 2012; 12: 35.
SchweigerT,Nikolowsky C,Starlinger P, et al. Stromal expression ofheat-shockprotein 27 is associated with worse clinical outcome in patients with colorectal cancer lung metastases. PLoS One 2015; 10: e0120724.
KnowlesLM,GurskiLA,Engel C, et al. Integrin αvβ3 and fibronectin upregulate Slug in cancer cells to promote clot invasion and metastasis. Cancer Res 2013; 73: 6175–84.
Lv H, Liu R, Fu J, et al.Epithelial cell-derived periostin functions as a tumor suppressor in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14ARF/Mdm2 signaling pathway. Cell Cycle 2014; 13: 2962–74.
Zhu J, Pan X, Zhang Z, et al. Downregulation of integrinlinked kinase inhibits epithelial-to-mesenchymal transition and metastasis in bladder cancer cells. Cell Signal 2012; 24: 1323–32.
Yang J, Zhang X, Zhang Y, et al. HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J Exp Clin Cancer Res 2016; 35: 26.
Huang M, Wang L, Chen J, et al. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxiainducible factor-1α is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery. Int J Oncol 2016; 48: 2144–54.
Peranzoni E, Rivas-Caicedo A, Bougherara H, et al. Positive and negative influence of the matrix architecture on antitumor immune surveillance. Cell Mol Life Sci 2013; 70: 4431–48.
Monboisse JC,Oudart JB,Ramont L, et al. Matrikines from basement membrane collagens: a new anti-cancer strategy. Biochim Biophys Acta 2014; 1840: 2589–98.
Huang JY, Cheng YJ, Lin YP, et al. Extracellular matrix of glioblastoma inhibits polarization and transmigration of T cells: the role of tenascin-C in immune suppression. J Immunol 2010; 185: 1450–9.
Caruana I, Savoldo B, Hoyos V, et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med 2015; 21: 524–9.
Wolf K,Müller R,Borgmann S, et al. Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. Blood 2003; 102: 3262–9.
Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 2013; 13: 788–99.
Ciechomska M, Wilson CL, Floudas A, et al. Antigen-specific B lymphocytes acquire proteoglycan aggrecan from cartilage extracellular matrix resulting in antigen presentation and CD4+ T-cell activation. Immunology 2014; 141: 70–8.
Fricke I, Gabrilovich DI. Dendritic cells and tumor microenvironment: a dangerous liaison. Immunol Invest 2006; 35:
–83.
Wight TN, Kang I, Merrilees MJ. Versican and the control of inflammation. Matrix Biol 2014; 35: 152–61.
Onken J, Moeckel S, Leukel P, et al. Versican isoform V1 regulates proliferation and migration in high-grade gliomas. J Neurooncol 2014; 120: 73–83.
Faurobert E, Bouin AP, Albiges-Rizo C. Microenvironment, tumor cell plasticity, and cancer. Curr Opin Oncol 2015;
: 64–70.
Hartmann N, Giese NA, Giese T, et al. Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. Clin Cancer Res 2014; 20: 3422–33.
Górski A, Castronovo V, Stepień-Sopniewska B, et al. Depressed immune surveillance against cancer: role of deficient T cell: extracellular matrix interactions. Cell Adhes Commun 1994; 2: 225–33.
Jiang D, Lim SY. Influence of immune myeloid cells on the extracellular matrix during cancer metastasis. Cancer Microenviron 2016; 9: 45–61.
Acerbi I, Cassereau L, Dean I, et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb) 2015; 7: 1120–34.
Narunsky L, Oren R, Bochner F, et al. Imaging aspects of the tumor stroma with therapeutic implications. Pharmacol Ther 2014;
: 192–208.
Wang Z, Li S, Li F, et al. Identification and function analysis of a novel vascular endothelial growth factor, LvVEGF3, in the Pacific whiteleg shrimp Litopenaeus vannamei. Dev Comp Immunol 2016; 63: 111–20.
Luoto KR, Kumareswaran R, Bristow RG. Tumor hypoxia as a driving force in genetic instability. Genome Integr 2013; 4: 5.
Jin F, Brockmeier U, Otterbach F, et al. New insight into the SDF-1/CXCR4 axis in a breast carcinoma model: hypoxia-induced endothelial SDF-1 and tumor cell CXCR4 are required fortumor cell intravasation. Mol Cancer Res 2012; 10: 1021–31.
Zhao BC, Wang ZJ, Mao WZ, et al. CXCR4/SDF-1 axis is involved in lymph node metastasis of gastric carcinoma. World J Gastroenterol 2011; 17: 2389–96.
Nagy JA, Dvorak AM, Dvorak HF. Vascular hyperpermeability, angiogenesis, and stroma generation. Cold Spring Harb Perspect Med 2012; 2: a006544.
Balcioglu HE, van de Water B, Danen EH. Tumor-induced remote ECM network orientation steers angiogenesis. Sci Rep 2016; 6: 22580.
Nagy JA, Shih SC, Wong WH, et al. Chapter 3. The adenoviral vector angiogenesis/lymphangiogenesis assay. Methods Enzymol 2008; 444: 43–64.
Dvorak HF. Tumor stroma, tumor blood vessels, and antiangiogenesis therapy. Cancer J 2015; 21: 237–43.
Huang Y, Song N, Ding Y, et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res 2009; 69: 7529–37.
Hayashi Y, Call MK, Chikama T, et al. Lumican is required for neutrophil extravasation following corneal injury and wound healing. J Cell Sci 2010; 123: 2987–95.
Nikitovic D, Papoutsidakis A, Karamanos NK, et al. Lumican affects tumor cell functions, tumor-ECM interactions, angiogenesis and inflammatory response. Matrix Biol 2014; 35: 206–14.
Liu Y, Li F, Gao F, et al. Periostin promotes tumor angiogenesis in pancreatic cancer via Erk/VEGF signaling. Oncotarget 2016 [Epub ahead of print].
Wang Z, Xiong S, Mao Y, et al. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis. J Pathol 2016 [Epub ahead of print].
Shin Y, Han S, Chung E, et al.Intratumoral phenotypic heterogeneity as an encourager of cancer invasion. Integr Biol (Camb) 2014; 6: 654–61.
