Cancer-associated fibroblasts mediate cancer progression and remodel the tumouroid stroma.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
18
11
2019
accepted:
17
06
2020
revised:
11
05
2020
pubmed:
10
7
2020
medline:
24
3
2021
entrez:
10
7
2020
Statut:
ppublish
Résumé
Cancer-associated fibroblasts (CAFs) are highly differentiated and heterogeneous cancer-stromal cells that promote tumour growth, angiogenesis and matrix remodelling. We utilised an adapted version of a previously developed 3D in vitro model of colorectal cancer, composed of a cancer mass and the surrounding stromal compartment. We compared cancer invasion with an acellular stromal surround, a "healthy" or normal cellular stroma and a cancerous stroma. For the cancerous stroma, we incorporated six patient-derived CAF samples to study their differential effects on cancer growth, vascular network formation and remodelling. CAFs enhanced the distance and surface area of the invasive cancer mass whilst inhibiting vascular-like network formation. These processes correlated with the upregulation of hepatocyte growth factor (HGF), metallopeptidase inhibitor 1 (TIMP1) and fibulin-5 (FBLN5). Vascular remodelling of previously formed endothelial structures occurred through the disruption of complex networks, and was associated with the upregulation of vascular endothelial growth factor (VEGFA) and downregulation in vascular endothelial cadherin (VE-Cadherin). These results support, within a biomimetic 3D, in vitro framework, the direct role of CAFs in promoting cancer invasion, and their key function in driving vasculogenesis and angiogenesis.
Sections du résumé
BACKGROUND
Cancer-associated fibroblasts (CAFs) are highly differentiated and heterogeneous cancer-stromal cells that promote tumour growth, angiogenesis and matrix remodelling.
METHODS
We utilised an adapted version of a previously developed 3D in vitro model of colorectal cancer, composed of a cancer mass and the surrounding stromal compartment. We compared cancer invasion with an acellular stromal surround, a "healthy" or normal cellular stroma and a cancerous stroma. For the cancerous stroma, we incorporated six patient-derived CAF samples to study their differential effects on cancer growth, vascular network formation and remodelling.
RESULTS
CAFs enhanced the distance and surface area of the invasive cancer mass whilst inhibiting vascular-like network formation. These processes correlated with the upregulation of hepatocyte growth factor (HGF), metallopeptidase inhibitor 1 (TIMP1) and fibulin-5 (FBLN5). Vascular remodelling of previously formed endothelial structures occurred through the disruption of complex networks, and was associated with the upregulation of vascular endothelial growth factor (VEGFA) and downregulation in vascular endothelial cadherin (VE-Cadherin).
CONCLUSIONS
These results support, within a biomimetic 3D, in vitro framework, the direct role of CAFs in promoting cancer invasion, and their key function in driving vasculogenesis and angiogenesis.
Identifiants
pubmed: 32641866
doi: 10.1038/s41416-020-0973-9
pii: 10.1038/s41416-020-0973-9
pmc: PMC7524802
doi:
Substances chimiques
Vascular Endothelial Growth Factor A
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1178-1190Subventions
Organisme : Department of Health
ID : II-LA-0813-20002
Pays : United Kingdom
Références
Chang, C. H., Qiu, J., O’Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
pubmed: 4864363
pmcid: 4864363
Shiga, K., Hara, M., Nagasaki, T., Sato, T. & Takahashi, H. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers 7, 2443–2458 (2015).
pubmed: 26690480
pmcid: 4695902
Augsten, M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front. Oncol. 4, 1–34 (2014).
Tommelein, J., Verset, L., Boterberg, T., Demetter, P., Bracke, M. & De Wever, O. Cancer-associated fibroblasts connect metastasis-promoting communication in colorectal cancer. Front. Oncol. 5, 1–11 (2015).
Attieh, Y. & Vignjevic, D. M. The hallmarks of CAFs in cancer invasion. Eur. J. Cell Biol. 95, 493–502 (2016).
pubmed: 27575401
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Publ. Gr. 16, 582–598 (2016).
Reid, S. E., Kay, E. J., Neilson, L. J., Henze, A., Serneels, J., McGhee, E. J. et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J. 36, 2373–2389 (2017).
pubmed: 28694244
pmcid: 5556271
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
pubmed: 28117416
pmcid: 5480600
Cirri, P. & Chiarugi, P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 31, 195–208 (2012).
pubmed: 22101652
Darby, I. A., Laverdet, B., Bonté, F. & Desmoulière, A. Fibroblasts and myofibroblasts in wound healing. Clin. Cosmet. Investig. Dermatol. 7, 301–311 (2014).
pubmed: 25395868
pmcid: 4226391
Cirri, P. & Chiarugi, P. Cancer associated fibroblasts: the dark side of the coin. Am. J. 1 Cancer Res. 1, 482–497 (2011).
Madsen, C. D., Pedersen, J. T., Venning, F. A., Singh, L. B., Charras, G., Cox, T. R. et al. Hypoxia and loss of PHD 2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis. EMBO Rep. 16, 1394–1408 (2015).
pubmed: 26323721
pmcid: 4662858
Glentis, A., Oertle, P., Mariani, P., Chikina, A., Marjou, F. El, Attieh, Y. et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 8, 1–13 (2017).
Maller, O., Dufort, C. C. & Weaver, V. M. YAP forces fibroblasts to feel the tension. Nat. Cell Biol. 15, 570–572 (2013).
pubmed: 23728464
Calvo, F., Ege, N., Grande-Garcia, A., Hooper, S., Jenkins, R. P., Chaudhry, S. I. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15, 637–646 (2013).
doi: 10.1038/ncb2756
Cao, H., Xu, E., Liu, H., Wan, L. & Lai, M. Epithelial-mesenchymal transition in colorectal cancer metastasis: a system review. Pathol. Res. Pr. 211, 557–569 (2015).
Kakarla, S., Song, X.-T. & Gottschalk, S. Cancer-associated fibroblasts as targets for immunotherapy. Immunotherapy 4, 1129–1138 (2012).
pubmed: 23194363
pmcid: 3568630
Liu, T., Lin, B. & Qin, J. Carcinoma-associated fibroblasts promoted tumor spheroid invasion on a microfluidic 3D co-culture device. Lab. Chip 10, 1671–1677 (2010).
pubmed: 20414488
Pape, J., Magdeldin, T., Ali, M., Walsh, C., Lythgoe, M., Emberton, M. et al. Cancer invasion regulates vascular complexity in a three-dimensional biomimetic model. Eur. J. Cancer 119, 179–193 (2019).
pubmed: 31470251
Magdeldin, T., López-Dávila, V., Pape, J., Cameron, G. W. W., Emberton, M., Loizidou, M. et al. Engineering a vascularised 3D in vitro model of cancer progression. Sci. Rep. 7, 1–9 (2017).
Stamati, K., Priestley, J. V., Mudera, V. & Cheema, U. Laminin promotes vascular network formation in 3D in vitro collagen scaffolds by regulating VEGF uptake. Exp. Cell Res. 327, 68–77 (2014).
pubmed: 24907654
pmcid: 4155934
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 9, 676–682 (2012).
pubmed: 22743772
pmcid: 22743772
Rio, D. C., Ares, M., Hannon, G. J. & Nilsen, T. W. Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb. Protoc. 5, 1–4 (2010).
Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative CTmethod. Nat. Protoc. 3, 1101–1108 (2008).
pubmed: 18546601
pmcid: 18546601
Bolander, J., Chai, Y. C., Geris, L., Schrooten, J., Lambrechts, D., Roberts, S. J. et al. Early BMP, Wnt and Ca2+/PKC pathway activation predicts the bone forming capacity of periosteal cells in combination with calcium phosphates. Biomaterials 86, 106–118 (2016).
pubmed: 26901484
Choi, S. Y., Sung, R., Lee, S. J., Lee, T. G., Kim, N., Yoon, S. M. et al. Podoplanin, α-smooth muscle actin or S100A4 expressing cancer-associated fibroblasts are associated with different prognosis in colorectal cancers. J. Korean Med. Sci. 28, 1293–1301 (2013).
pubmed: 24015033
pmcid: 3763102
Madar, S., Goldstein, I. & Rotter, V. “Cancer associated fibroblasts”—more than meets the eye. Trends Mol. Med. 19, 447–453 (2013).
pubmed: 23769623
Knüpfer, H. & Preiss, R. Serum interleukin-6 levels in colorectal cancer patients-a summary of published results. Int J. Colorectal Dis. 25, 135–140 (2010).
pubmed: 19898853
Talele, N. P., Fradette, J., Davies, J. E., Kapus, A. & Hinz, B. Expression of α-smooth muscle actin determines the fate of mesenchymal stromal cells. Stem Cell Rep. 4, 1016–1030 (2015).
Hamada, K., Monnai, M., Kawai, K., Nishime, C., Kito, C., Miyazaki, N. et al. Liver metastasis models of colon cancer for evaluation of drug efficacy using NOD/Shi-scid IL2Rgammanull (NOG) mice. Int. J. Oncol. 32, 153–159 (2008).
pubmed: 18097554
Roudsari, L. C. & West, J. L. Studying the influence of angiogenesis in in vitro cancer model systems. Adv. Drug Deliv. Rev. 97, 250–259 (2016).
pubmed: 26571106
Vestweber, D. VE-cadherin: The major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb. Vasc. Biol. 28, 223–232 (2008).
pubmed: 18162609
Liao, Y., Zhao, H., Liu, Q. & Peng, R. Fibulin-5 inhibits the cell proliferation, migration and angiogenesis in glioma. Int. J. Clin. Exp. Pathol. 9, 8943–8952 (2016).
Sullivan, K. M., Bissonnette, R., Yanagisawa, H., Hussain, S. N. & Davis, E. C. Fibulin-5 functions as an endogenous angiogenesis inhibitor. Lab. Investig. 87, 818–827 (2007).
pubmed: 17607303
Albig, A. R. & Schiemann, W. P. Fibulin-5 antagonizes vascular endothelial growth factor (VEGF) signaling and angiogenic sprouting by endothelial cells. DNA Cell Biol. 23, 367–379 (2004).
pubmed: 15231070
Jeanes, A., Gottardi, C. J. & Yap, A. S. Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27, 6920–6929 (2008).
pubmed: 19029934
pmcid: 2745643
Grugan, K. D., Miller, C. G., Yao, Y., Michaylira, C. Z., Ohashi, S., Klein-Szanto, A. J. et al. Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. Proc. Natl Acad. Sci. USA 107, 11026–11031 (2010).
pubmed: 20534479
Zhang, Y., Tang, H., Cai, J., Zhang, T., Guo, J., Feng, D. et al. Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett. 303, 47–55 (2011).
pubmed: 21310528
Hwang, R. F., Moore, T., Arumugam, T., Ramachandran, V., Amos, K. D., Rivera, A. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926 (2008).
pubmed: 18245495
pmcid: 2519173
Barcus, C. E., Keely, P. J., Eliceiri, K. W. & Schuler, L. A. Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. J. Biol. Chem. 288, 12722–12732 (2013).
pubmed: 23530035
pmcid: 3642318
Wei, S. C. & Yang, J. Forcing through tumor metastasis: the interplay between tissue rigidity and epithelial-mesenchymal transition. Trends Cell Biol. 26, 111–120 (2016).
pubmed: 26508691
Tang, D., Gao, J., Wang, S., Ye, N., Chong, Y., Huang, Y. et al. Cancer-associated fibroblasts promote angiogenesis in gastric cancer through galectin-1 expression. Tumor Biol. 37, 1889–1899 (2016).
Hallaq, H. A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels. Development 131, 5197–5209 (2004).
pubmed: 15459110
Kioi, M., Vogel, H., Schultz, G., Hoffman, R. M., Harsh, G. R. & Brown, J. M. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010).
pubmed: 20179352
pmcid: 2827954
Weis, S., Cui, J., Barnes, L. & Cheresh, D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J. Cell Biol. 167, 223–229 (2004).
pubmed: 15504909
pmcid: 2172541
Li, W.-W., Wang, H., Nie, X., Liu, Y., Han, M. & Li, B.-H. Human colorectal cancer cells induce vascular smooth muscle cell apoptosis in an exocrine manner. Oncotarget 8, 62049–62056 (2017).
pubmed: 28977925
pmcid: 5617485
De Francesco, E. M., Lappano, R., Santolla, M. F., Marsico, S., Caruso, A. & Maggiolini, M. HIF-1α/GPER signaling mediates the expression of VEGF induced by hypoxia in breast cancer associated fibroblasts (CAFs). Breast Cancer Res. 15, 1–18 (2013).
Alarcón, T., Owen, M. R., Byrne, H. M. & Maini, P. K. Multiscale modelling of tumour growth and therapy: the influence of vessel normalisation on chemotherapy. Comput. Math. Methods Med. 7, 85–119 (2006).
Torres, S., Bartolomé, R. A., Mendes, M., Barderas, R., Fernandez-Aceñero, M. J., Peláez-García, A. et al. Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin. Cancer Res. 21, 6006–6019 (2013).
Ueno, H., Murphy, J., Jass, J. R., Mochizuki, H. & Talbot, I. C. Tumour “budding” as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 40, 127–132 (2002).
pubmed: 11952856
Pampaloni, F., Reynaud, E. G. & Stelzer, E. H. K. The third dimension bridges the gap between cell culture and live tissue. Nat. Rev. Mol. Cell Biol. 8, 839–845 (2007).
pubmed: 17684528
You, W. K. & McDonald, D. M. The hepatocyte growth factor/c-met signaling pathway as a therapeutic target to inhibit angiogenesis. J. Biochem. Mol. Biol. 41, 833–839 (2008).