Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells

Ping-Pui Wong, Jose M Munoz-Felix, Maruan Hijazi, Hyojin Kim, Stephen Robinson, Beatriz De Luxan-Delgado, Irene Rodiguez-Hernandez, Oscar Maiques, Ya-Ming Meng, Qiong Meng, Natalia Bodrug, Matthew Scott Dukinfield, Louise E Reynolds, George Elia, Andrew Clear, Catherine Harwood, Yu Wang, James J Campbell, Rajinder Singh, Penglie ZhangThomas J Schall, Kylie P Matchett, Neil Henderson, Peter W Szlosarek, Sally Dreger, Sally Smith, J Louise Jones, John G Gribben, Pedro R Cutillas, Pascal Meier, Victoria Sanz-Moreno, Kairbaan Hodivala-Dilke

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Abstract

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-β3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-β3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell β3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by β3-integrin, providing a previously unrecognized mechanism of cancer growth control.
Original languageEnglish
Pages (from-to)1346-1363.e21
Number of pages18
JournalCell
Volume181
Issue number6
Early online date29 May 2020
DOIs
Publication statusPublished - 11 Jun 2020

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