alternative TGFβ signaling; endothelial cells; liver metastases
Abstract :
[en] Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.
Engstrand J, Nilsson H, Stromberg C, Jonas E, Freedman J. Colorectal cancer liver metastases - a population-based study on incidence, management and survival. BMC Cancer. 2018; 18: 78.
Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014; 14: 611-22.
Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012; 21: 309-22.
Ronca R, Van Ginderachter JA, Turtoi A. Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes. Curr Opin Oncol. 2018; 30: 45-53.
Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 1996; 10: 2462-77.
Jung B, Staudacher JJ, Beauchamp D. Transforming growth factor beta superfamily signaling in development of colorectal cancer. Gastroenterology. 2017; 152: 36-52.
Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012; 22: 571-84.
Xu Y, Pasche B. TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet. 2007; 16 Spec No 1: R14-20.
Luo J, Chen XQ, Li P. The role of TGF-beta and its receptors in gastrointestinal cancers. Transl Oncol. 2019; 12: 475-84.
de Miranda NF, van Dinther M, van den Akker BE, van Wezel T, ten Dijke P, Morreau H. Transforming growth factor beta signaling in colorectal cancer cells with microsatellite instability despite biallelic mutations in TGFBR2. Gastroenterology. 2015; 148: 1427-37 e8.
Skonier J, Neubauer M, Madisen L, Bennett K, Plowman GD, Purchio AF. cDNA cloning and sequence analysis of beta ig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-beta. DNA Cell Biol. 1992; 11: 511-22.
Huber O, Sumper M. Algal-CAMs: isoforms of a cell adhesion molecule in embryos of the alga Volvox with homology to Drosophila fasciclin I. EMBO J. 1994; 13: 4212-22.
Nieberler M, Reuning U, Reichart F, Notni J, Wester HJ, Schwaiger M, et al. Exploring the role of RGD-recognizing integrins in cancer. Cancers (Basel). 2017; 9.
Yokobori T, Nishiyama M. TGF-beta signaling in gastrointestinal cancers: progress in basic and clinical research. J Clin Med. 2017; 6.
Zhang Y, Wen G, Shao G, Wang C, Lin C, Fang H, et al. TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res. 2009; 69: 37-44.
Ma C, Rong Y, Radiloff DR, Datto MB, Centeno B, Bao S, et al. Extracellular matrix protein betaig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation. Genes Dev. 2008; 22: 308-21.
Waltregny D, Bellahcene A, Van Riet I, Fisher LW, Young M, Fernandez P, et al. Prognostic value of bone sialoprotein expression in clinically localized human prostate cancer. J Natl Cancer Inst. 1998; 90: 1000-8.
Grillet F, Bayet E, Villeronce O, Zappia L, Lagerqvist EL, Lunke S, et al. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture. Gut. 2017; 66: 1802-10.
Giraud J, Failla LM, Pascussi JM, Lagerqvist EL, Ollier J, Finetti P, et al. Autocrine secretion of progastrin promotes the survival and self-renewal of colon cancer stem-like cells. Cancer Res. 2016; 76: 3618-28.
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012; 9: 676-82.
Turtoi A, Blomme A, Debois D, Somja J, Delvaux D, Patsos G, et al. Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies. Hepatology. 2014; 59: 924-34.
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010; 8: e1000412.
Vosjan MJ, Perk LR, Visser GW, Budde M, Jurek P, Kiefer GE, et al. Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyldesferrioxamine. Nat Protoc. 2010; 5: 739-43.
Price JE, Daniels LM, Campbell DE, Giavazzi R. Organ distribution of experimental metastases of a human colorectal carcinoma injected in nude mice. Clin Exp Metastasis. 1989; 7: 55-68.
Cordenonsi M, Dupont S, Maretto S, Insinga A, Imbriano C, Piccolo S. Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell. 2003; 113: 301-14.
Johansson J, Sahin C, Pestoff R, Ignatova S, Forsberg P, Edsjo A, et al. A novel SMAD4 mutation causing severe juvenile polyposis syndrome with protein losing enteropathy, immunodeficiency, and hereditary haemorrhagic telangiectasia. Case Rep Gastrointest Med. 2015; 2015: 140616.
Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001; 344: 1196-206.
Song J, Chen W, Cui X, Huang Z, Wen D, Yang Y, et al. CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer. Theranostics. 2020; 10: 2327-41.
Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21: 1350-6.
Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther. 2015; 147: 22-31.
Buckhaults P, Rago C, St Croix B, Romans KE, Saha S, Zhang L, et al. Secreted and cell surface genes expressed in benign and malignant colorectal tumors. Cancer Res. 2001; 61: 6996-7001.
Greening DW, Kapp EA, Ji H, Speed TP, Simpson RJ. Colon tumour secretopeptidome: insights into endogenous proteolytic cleavage events in the colon tumour microenvironment. Biochim Biophys Acta. 2013; 1834: 2396-407.
Yu H, Wergedal JE, Zhao Y, Mohan S. Targeted disruption of TGFBI in mice reveals its role in regulating bone mass and bone size through periosteal bone formation. Calcif Tissue Int. 2012; 91: 81-7.
Stahl PJ, Felsen D. Transforming growth factor-beta, basement membrane, and epithelial-mesenchymal transdifferentiation: implications for fibrosis in kidney disease. Am J Pathol. 2001; 159: 1187-92.
Ilyas M, Efstathiou JA, Straub J, Kim HC, Bodmer WF. Transforming growth factor beta stimulation of colorectal cancer cell lines: type II receptor bypass and changes in adhesion molecule expression. Proc Natl Acad Sci U S A. 1999; 96: 3087-91.
Baker K, Raut P, Jass JR. Microsatellite unstable colorectal cancer cell lines with truncating TGFbetaRII mutations remain sensitive to endogenous TGFbeta. J Pathol. 2007; 213: 257-65.
Zhang L, Zhou F, ten Dijke P. Signaling interplay between transforming growth factor-beta receptor and PI3K/AKT pathways in cancer. Trends Biochem Sci. 2013; 38: 612-20.
Moustakas A, Heldin CH. Mechanisms of TGFbeta-induced epithelial-mesenchymal transition. J Clin Med. 2016; 5.
Chen Y, Liu P, Sun P, Jiang J, Zhu Y, Dong T, et al. Oncogenic MSH6-CXCR4-TGFB1 feedback loop: a novel therapeutic target of photothermal therapy in glioblastoma multiforme. Theranostics. 2019; 9: 1453-73.
