TY - JOUR
T1 - Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy
AU - Kim, Jiha
AU - de Sampaio, Pedro Correa
AU - Lundy, Donna Marie
AU - Peng, Qian
AU - Evans, Kurt W.
AU - Sugimoto, Hikaru
AU - Gagea, Mihai
AU - Kienast, Yvonne
AU - do Amaral, Nayra Soares
AU - Rocha, Rafael M.
AU - Eikesdal, Hans Petter
AU - Lønning, Per Eystein
AU - Meric-Bernstam, Funda
AU - LeBleu, Valerie
N1 - Funding Information:
We wish to thank Markus Thomas and Joachim Muller (Roche) for providing us with the anti-ANG2 antibody and Laura Gibson and Komal Vadnagara for animal experiment support. We wish to thank Julie Carstens for her useful discussions on multispectral imaging and analyses and Lisa Norberg for her continuous support regarding laboratory equipment and supplies as well as managerial support. We wish to thank Edward Chang (Institute of Applied Cancer Science, MD Anderson Cancer Center) for help with scanning histological slides. We wish to also thank Raghu Kalluri for his continuous support and insightful discussion and comments on the study. JK and this study were primarily supported by the NIH grant CA155370. The study was also supported by the University of Texas Faculty Science and Technology Acquisition and Retention (STARs) Program to RK and VSL. VSL is also supported by the NIH/ National Cancer institute Cancer Center Support Grant New Faculty Award (P30CA016672) and UT MD Anderson Cancer Center through the Khalifa Bin Zayed Al Nahyan Foundation. HPE and PEL are supported by grants from Helse Vest, the Bergen Medical Research Foundation, the Norwegian Cancer Society, and the Rieber Foundation, Norway.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/12/22
Y1 - 2016/12/22
N2 - Angiogenesis and co-optive vascular remodeling are prerequisites of solid tumor growth. Vascular heterogeneity, notably perivascular composition, may play a critical role in determining the rate of cancer progression. The contribution of vascular pericyte heterogeneity to cancer progression and therapy response is unknown. Here, we show that angiopoietin-2 (Ang2) orchestrates pericyte heterogeneity in breast cancer with an effect on metastatic disease and response to chemotherapy. Using multispectral imaging of human breast tumor specimens, we report that perivascular composition, as defined by the ratio of PDGFRβ- and desmin+ pericytes, provides information about the response to epirubicin but not paclitaxel. Using 17 distinct patient-derived breast cancer xenografts, we demonstrate a cancer cell-derived influence on stromal Ang2 production and a cancer cell-defined control over tumor vasculature and perivascular heterogeneity. The aggressive features of tumors and their distinct response to therapies may thus emerge by the cancer cell- defined engagement of distinct and heterogeneous angiogenic programs.
AB - Angiogenesis and co-optive vascular remodeling are prerequisites of solid tumor growth. Vascular heterogeneity, notably perivascular composition, may play a critical role in determining the rate of cancer progression. The contribution of vascular pericyte heterogeneity to cancer progression and therapy response is unknown. Here, we show that angiopoietin-2 (Ang2) orchestrates pericyte heterogeneity in breast cancer with an effect on metastatic disease and response to chemotherapy. Using multispectral imaging of human breast tumor specimens, we report that perivascular composition, as defined by the ratio of PDGFRβ- and desmin+ pericytes, provides information about the response to epirubicin but not paclitaxel. Using 17 distinct patient-derived breast cancer xenografts, we demonstrate a cancer cell-derived influence on stromal Ang2 production and a cancer cell-defined control over tumor vasculature and perivascular heterogeneity. The aggressive features of tumors and their distinct response to therapies may thus emerge by the cancer cell- defined engagement of distinct and heterogeneous angiogenic programs.
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U2 - 10.1172/jci.insight.90733
DO - 10.1172/jci.insight.90733
M3 - Article
C2 - 28018977
AN - SCOPUS:85021932495
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 21
M1 - e90733
ER -