Abstract
The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27IGF−IR murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen α1 and α2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/α2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by small-interfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.
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Abbreviations
- BM:
-
basement membrane
- cDNA:
-
complementary DNA
- CRC:
-
colorectal carcinoma
- ECM:
-
extracellular matrix
- FAK:
-
focal adhesion kinase
- FF-PE:
-
formalin-fixed and paraffin-embedded
- HIF:
-
hypoxia-inducible factor
- IGF:
-
insulin-like growth factor
- IGF-IR:
-
insulin-like growth factor-1 receptor
- IHC:
-
immunohistochemistry
- pFAK:
-
phosphorylated-focal adhesion kinase
- RT–PCR:
-
reverse transcriptase–PCR
- siRNA:
-
small-interfering RNA
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labeling
References
All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ, Larsson O . (2002). Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci 43: 1–8.
Andersson S, D'Arcy P, Larsson O, Sehat B . (2009). Focal adhesion kinase (FAK) activates and stabilizes IGF-1 receptor. Biochem Biophys Res Commun 387: 36–41.
Barsky SH, Togo S, Garbisa S, Liotta LA . (1983). Type IV collagenase immunoreactivity in invasive breast carcinoma. Lancet 1: 296–297.
Beattie J, McIntosh L, van der Walle CF . (2010). Cross-talk between the insulin-like growth factor (IGF) axis and membrane integrins to regulate cell physiology. J Cell Physiol 224: 605–611.
Bissell DM . (2001). Chronic liver injury, TGF-beta, and cancer. Exp Mol Med 33: 179–190.
Boudreau NJ, Jones PL . (1999). Extracellular matrix and integrin signalling: the shape of things to come. Biochem J 339 (part 3): 481–488.
Brodt P, Fallavollita L, Khatib AM, Samani AA, Zhang D . (2001). Cooperative regulation of the invasive and metastatic phenotypes by different domains of the type I insulin-like growth factor receptor beta subunit. J Biol Chem 276: 33608–33615.
Brooks SA, Lomax-Browne HJ, Carter TM, Kinch CE, Hall DM . (2009). Molecular interactions in cancer cell metastasis. Acta Histochem 112: 3–25.
Catusse C, Polette M, Coraux C, Burlet H, Birembaut P . (2000). Modified basement membrane composition during bronchopulmonary tumor progression. J Histochem Cytochem 48: 663–669.
Clark RA . (2008). Synergistic signaling from extracellular matrix-growth factor complexes. J Invest Dermatol 128: 1354–1355.
Clemmons DR, Maile LA . (2003). Minireview: integral membrane proteins that function coordinately with the insulin-like growth factor I receptor to regulate intracellular signaling. Endocrinology 144: 1664–1670.
Decker NK, Abdelmoneim SS, Yaqoob U, Hendrickson H, Hormes J, Bentley M et al. (2008). Nitric oxide regulates tumor cell cross-talk with stromal cells in the tumor microenvironment of the liver. Am J Pathol 173: 1002–1012.
Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE . (2004). Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery 135: 555–562.
Eccles SA, Welch DR . (2007). Metastasis: recent discoveries and novel treatment strategies. Lancet 369: 1742–1757.
Edderkaoui M, Hong P, Lee JK, Pandol SJ, Gukovskaya AS . (2007). Insulin-like growth factor-I receptor mediates the prosurvival effect of fibronectin. J Biol Chem 282: 26646–26655.
Enns A, Gassmann P, Schluter K, Korb T, Spiegel HU, Senninger N et al. (2004). Integrins can directly mediate metastatic tumor cell adhesion within the liver sinusoids. J Gastrointest Surg 8: 1049–1059;discussion 1060.
Erin N, Wang N, Xin P, Bui V, Weisz J, Barkan GA et al. (2009). Altered gene expression in breast cancer liver metastases. Int J Cancer 124: 14.
Felding-Habermann B . (2003). Integrin adhesion receptors in tumor metastasis. Clin Exp Metastasis 20: 203–213.
Fenyvesi A . (2003). The prognostic significance of type IV collagen expression in colorectal carcinomas. Arch Oncol 11: 15.
Furukawa M, Raffeld M, Mateo C, Sakamoto A, Moody TW, Ito T et al. (2005). Increased expression of insulin-like growth factor I and/or its receptor in gastrinomas is associated with low curability, increased growth, and development of metastases. Clin Cancer Res 11: 3233–3242.
Gabarra-Niecko V, Schaller MD, Dunty JM . (2003). FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev 22: 359–374.
Goel HL, Breen M, Zhang J, Das I, Aznavoorian-Cheshire S, Greenberg NM et al. (2005). beta1A integrin expression is required for type 1 insulin-like growth factor receptor mitogenic and transforming activities and localization to focal contacts. Cancer Res 65: 6692–6700.
Goel HL, Fornaro M, Moro L, Teider N, Rhim JS, King M et al. (2004). Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins. J Cell Biol 166: 407–418.
Gualberto A, Pollak M . (2009). Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28: 3009–3021.
Gulubova MV . (2004). Collagen type IV, laminin, alpha-smooth muscle actin (alphaSMA), alpha1 and alpha6 integrins expression in the liver with metastases from malignant gastrointestinal tumours. Clin Exp Metastasis 21: 485–494.
Gydee H, O'Neill JT, Patel A, Bauer AJ, Tuttle RM, Francis GL . (2004). Differentiated thyroid carcinomas from children and adolescents express IGF-I and the IGF-I receptor (IGF-I-R). Cancers with the most intense IGF-I-R expression may be more aggressive. Pediatr Res 55: 709–715.
Habeck M . (2001). Targeting the extracellular matrix to stop tumour progression. Drug Discov Today 6: 1077–1078.
Havenith MG, Arends JW, Simon R, Volovics A, Wiggers T, Bosman FT . (1988). Type IV collagen immunoreactivity in colorectal cancer. Prognostic value of basement membrane deposition. Cancer 62: 2207–2211.
Hiki Y, Iyama K, Tsuruta J, Egami H, Kamio T, Suko S et al. (2002). Differential distribution of basement membrane type IV collagen alpha1(IV), alpha2(IV), alpha5(IV) and alpha6(IV) chains in colorectal epithelial tumors. Pathol Int 52: 224–233.
Iglesias-de la Cruz MC, Ziyadeh FN, Isono M, Kouahou M, Han DC, Kalluri R et al. (2002). Effects of high glucose and TGF-[bgr]1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int 62: 901–913.
Ikeda K, Iyama K, Ishikawa N, Egami H, Nakao M, Sado Y et al. (2006). Loss of expression of type IV collagen alpha5 and alpha6 chains in colorectal cancer associated with the hypermethylation of their promoter region. Am J Pathol 168: 856–865.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U et al. (2003). Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4: 249–264.
Jeschke MG, Schubert T, Krickhahn M, Polykandriotis E, Klein D, Perez-Polo JR et al. (2005). Interaction of exogenous liposomal insulin-like growth factor-I cDNA gene transfer with growth factors on collagen expression in acute wounds. Wound Repair Regen 13: 269–277.
Kahana O, Micksche M, Witz IP, Yron I . (2002). The focal adhesion kinase (P125FAK) is constitutively active in human malignant melanoma. Oncogene 21: 3969–3977.
Khoshnoodi J, Pedchenko V, Hudson BG . (2008). Mammalian collagen IV. Microsc Res Tech 71: 357–370.
Krensel K, Lichtner RB . (1999). Selective increase of alpha2-integrin sub-unit expression on human carcinoma cells upon EGF-receptor activation. Int J Cancer 80: 546–552.
Kurban G, Duplan E, Ramlal N, Hudon V, Sado Y, Ninomiya Y et al. (2008). Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. Oncogene 27: 1004–1012.
Liu G, Meng X, Jin Y, Bai J, Zhao Y, Cui X et al. (2008). Inhibitory role of focal adhesion kinase on anoikis in the lung cancer cell A549. Cell Biol Int 32: 663–670.
Liu W, Bloom DA, Cance WG, Kurenova EV, Golubovskaya VM, Hochwald SN . (2008). FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. Carcinogenesis 29: 1096–1107.
Long L, Rubin R, Baserga R, Brodt P . (1995). Loss of the metastatic phenotype in murine carcinoma cells expressing an antisense RNA to the insulin-like growth factor receptor. Cancer Res 55: 1006–1009.
Macri L, Silverstein D, Clark RA . (2007). Growth factor binding to the pericellular matrix and its importance in tissue engineering. Adv Drug Deliv Rev 59: 1366–1381.
Malinda KM, Kleinman HK . (1996). The laminins. Int J Biochem Cell Biol 28: 957–959.
Meir T, Dror R, Yu X, Qian J, Simon I, Pe'er J et al. (2007). Molecular characteristics of liver metastases from uveal melanoma. Invest Ophthalmol Vis Sci 48: 4890–4896.
Miner JH, Li C, Mudd JL, Go G, Sutherland AE . (2004). Compositional and structural requirements for laminin and basement membranes during mouse embryo implantation and gastrulation. Development 131: 2247–2256.
Miyamoto S, Yagi H, Yotsumoto F, Kawarabayashi T, Mekada E . (2008). Heparin-binding epidermal growth factor-like growth factor as a new target molecule for cancer therapy. Adv Exp Med Biol 622: 281–295.
Nadal C, Maurel J, Gascon P . (2007). Is there a genetic signature for liver metastasis in colorectal cancer? World J Gastroenterol 13: 5832–5844.
Nakano S, Iyama K, Ogawa M, Yoshioka H, Sado Y, Oohashi T et al. (1999). Differential tissular expression and localization of type IV collagen alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) chains and their mRNA in normal breast and in benign and malignant breast tumors. Lab Invest 79: 281–292.
Neubauer K, Saile B, Ramadori G . (2001). Liver fibrosis and altered matrix synthesis. Can J Gastroenterol 15: 187–193.
Oshima T, Akaike M, Yoshihara K, Shiozawa M, Yamamoto N, Sato T et al. (2008). Clinicopathological significance of the gene expression of matrix metalloproteinase-7, insulin-like growth factor-1, insulin-like growth factor-2 and insulin-like growth factor-1 receptor in patients with colorectal cancer: insulin-like growth factor-1 receptor gene expression is a useful predictor of liver metastasis from colorectal cancer. Oncol Rep 20: 359–364.
Paget S . (1989). The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8: 98–101.
Polette M, Nawrocki-Raby B, Gilles C, Clavel C, Birembaut P . (2004). Tumour invasion and matrix metalloproteinases. Crit Rev Oncol Hematol 49: 179–186.
Poschl E, Schlotzer-Schrehardt U, Brachvogel B, Saito K, Ninomiya Y, Mayer U . (2004). Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131: 1619–1628.
Rosenow F, Ossig R, Thormeyer D, Gasmann P, Schluter K, Brunner G et al. (2008). Integrins as antimetastatic targets of RGD-independent snake venom components in liver metastasis [corrected]. Neoplasia 10: 168–176.
Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N et al. (2003). TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34: 374–378.
Samani AA, Chevet E, Fallavollita L, Galipeau J, Brodt P . (2004). Loss of tumorigenicity and metastatic potential in carcinoma cells expressing the extracellular domain of the type 1 insulin-like growth factor receptor. Cancer Res 64: 3380–3385.
Samani AA, Yakar S, LeRoith D, Brodt P . (2007). The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28: 20–47.
Sastry SK, Burridge K . (2000). Focal adhesions: a nexus for intracellular signaling and cytoskeletal dynamics. Exp Cell Res 261: 25–36.
Sawai H, Okada Y, Funahashi H, Takahashi H, Matsuo Y, Yasuda A et al. (2008). Basement membrane proteins play an important role in the invasive processes of human pancreatic cancer cells. J Surg Res 144: 117–123.
Schapers RF, Pauwels RP, Havenith MG, Smeets AW, van den Brandt PA, Bosman FT . (1990). Prognostic significance of type IV collagen and laminin immunoreactivity in urothelial carcinomas of the bladder. Cancer 66: 2583–2588.
Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M . (1997). Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci USA 94: 13612–13617.
Shibue T, Weinberg RA . (2009). Integrin beta1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc Natl Acad Sci USA 106: 10290–10295.
Simpson CD, Anyiwe K, Schimmer AD . (2008). Anoikis resistance and tumor metastasis. Cancer Lett 272: 177–185.
Steeg PS . (2006). Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12: 895–904.
Steenhard BM, Isom K, Stroganova L, St John PL, Zelenchuk A, Freeburg PB et al. (2010). Deletion of von Hippel-Lindau in glomerular podocytes results in glomerular basement membrane thickening, ectopic subepithelial deposition of collagen [alpha]1[alpha]2[alpha]1(IV), expression of neuroglobin, and proteinuria. Am J Pathol 177: 84–96.
Tanaka K, Iyama K, Kitaoka M, Ninomiya Y, Oohashi T, Sado Y et al. (1997). Differential expression of alpha 1(IV), alpha 2(IV), alpha 5(IV) and alpha 6(IV) collagen chains in the basement membrane of basal cell carcinoma. Histochem J 29: 563–570.
Tang Y, Zhang D, Fallavollita L, Brodt P . (2003). Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor. Cancer Res 63: 1166–1171.
Theret N, Musso O, Turlin B, Lotrian D, Bioulac-Sage P, Campion JP et al. (2001). Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. Hepatology 34: 82–88.
Tian B, Li Y, Ji XN, Chen J, Xue Q, Ye SL et al. (2005). Basement membrane proteins play an active role in the invasive process of human hepatocellular carcinoma cells with high metastasis potential. J Cancer Res Clin Oncol 131: 80–86.
Ueda S, Hatsuse K, Tsuda H, Ogata S, Kawarabayashi N, Takigawa T et al. (2006). Potential crosstalk between insulin-like growth factor receptor type 1 and epidermal growth factor receptor in progression and metastasis of pancreatic cancer. Mod Pathol 19: 788–796.
van der Flier A, Sonnenberg A . (2001). Function and interactions of integrins. Cell Tissue Res 305: 285–298.
Vandenberg P, Kern A, Ries A, Luckenbill-Edds L, Mann K, Kuhn K . (1991). Characterization of a type IV collagen major cell binding site with affinity to the alpha 1 beta 1 and the alpha 2 beta 1 integrins. J Cell Biol 113: 1475–1483.
Vidal-Vanaclocha F . (2008). The prometastatic microenvironment of the liver. Cancer Microenviron 1: 113–129.
Wang N, Fallavollita L, Nguyen L, Burnier J, Rafei M, Galipeau J et al. (2009). Autologous bone marrow stromal cells genetically engineered to secrete an igf-I receptor decoy prevent the growth of liver metastases. Mol Ther 17: 1241–1249.
Wang JY, Grabacka M, Marcinkiewicz C, Staniszewska I, Peruzzi F, Khalili K et al. (2006a). Involvement of alpha1beta1 integrin in insulin-like growth factor-1-mediated protection of PC12 neuronal processes from tumor necrosis factor-alpha-induced injury. J Neurosci Res 83: 7–18.
Wang N, Thuraisingam T, Fallavollita L, Ding A, Radzioch D, Brodt P . (2006b). The secretory leukocyte protease inhibitor is a type 1 insulin-like growth factor receptor-regulated protein that protects against liver metastasis by attenuating the host proinflammatory response. Cancer Res 66: 3062–3070.
Wright GW, Simon RM . (2003). A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics 19: 2448–2455.
Xie Y, Skytting B, Nilsson G, Brodin B, Larsson O . (1999). Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype. Cancer Res 59: 3588–3591.
Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L et al. (2006). Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147: 5826–5834.
Yang C, Zeisberg M, Mosterman B, Sudhakar A, Yerramalla U, Holthaus K et al. (2003). Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors. Gastroenterology 124: 147–159.
Yoshimura K, Meckel KF, Laird LS, Chia CY, Park JJ, Olino KL et al. (2009). Integrin alpha2 mediates selective metastasis to the liver. Cancer Res 69: 7320–7328.
Zeisberg M, Kramer K, Sindhi N, Sarkar P, Upton M, Kalluri R . (2006). De-differentiation of primary human hepatocytes depends on the composition of specialized liver basement membrane. Mol Cell Biochem 283: 181–189.
Zha J, Lackner MR . (2010). Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin Cancer Res 16: 2512–2517.
Zhang D, Brodt P . (2003). Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling. Oncogene 22: 974–982.
Acknowledgements
We thank Dr Zelia Correa (Department of Ophthalmology, University of Cincinnati) for the kind gift of the uveal melanoma specimens, Dr Yoshihiko Yamada for collagen IV α1 and α2 plasmids, Dr Taina Pihlajaniemi for antibodies to collagen XVIII and Ms Boram Ham for her help with the submission. This work was supported by Grant MOP-81201 from the Canadian Institute for Health Research (to PB). JVB was supported by a doctoral fellowship from the Research Institute of the McGill University Health Center and PB is a recipient of the Stewart family award for Cancer Research.
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Burnier, J., Wang, N., Michel, R. et al. Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis. Oncogene 30, 3766–3783 (2011). https://doi.org/10.1038/onc.2011.89
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DOI: https://doi.org/10.1038/onc.2011.89
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