Cancer Burden Is Controlled by Mural Cell-β3-Integrin Regulated Crosstalk with Tumor Cells.
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Date
2020-06-11ICR Author
Author
Wong, P-P
Muñoz-Félix, JM
Hijazi, M
Kim, H
Robinson, SD
De Luxán-Delgado, B
Rodríguez-Hernández, I
Maiques, O
Meng, Y-M
Meng, Q
Bodrug, N
Dukinfield, MS
Reynolds, LE
Elia, G
Clear, A
Harwood, C
Wang, Y
Campbell, JJ
Singh, R
Zhang, P
Schall, TJ
Matchett, KP
Henderson, NC
Szlosarek, PW
Dreger, SA
Smith, S
Jones, JL
Gribben, JG
Cutillas, PR
Meier, P
Sanz-Moreno, V
Hodivala-Dilke, KM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Mice, Inbred C57BL
Humans
Mice
Neoplasms
Melanoma, Experimental
Integrin beta3
Tumor Burden
Signal Transduction
Cell Proliferation
Cell Movement
Female
Male
Research team
Cell Death and Immunity
Language
eng
Date accepted
2020-01-31
License start date
2020-06
Citation
Cell, 2020, 181 (6), pp. 1346 - 1363.e21
Publisher
CELL PRESS