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Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy
Jiha Kim, … , Funda Meric-Bernstam, Valerie S. LeBleu
Jiha Kim, … , Funda Meric-Bernstam, Valerie S. LeBleu
Published December 22, 2016
Citation Information: JCI Insight. 2016;1(21):e90733. https://doi.org/10.1172/jci.insight.90733.
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Research Article Angiogenesis Vascular biology

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

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Abstract

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.

Authors

Jiha Kim, Pedro Correa de Sampaio, Donna Marie Lundy, Qian Peng, Kurt W. Evans, Hikaru Sugimoto, Mihai Gagea, Yvonne Kienast, Nayra Soares do Amaral, Rafael Malagoli Rocha, Hans Petter Eikesdal, Per Eystein Lønning, Funda Meric-Bernstam, Valerie S. LeBleu

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Figure 1

Triple-negative and luminal breast cancer subtypes present distinct pericyte coverage.

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Triple-negative and luminal breast cancer subtypes present distinct peri...
(A) Flow chart highlighting the different steps of the phenotyping analysis of multispectral image cubes using the InForm image analysis software. RGB multispectral images are spectrally unmixed into their different fluorescent components and segmented in three image regions based on the CD31 and DAPI staining patterns: blank (blue), perivascular (green), and other (red). Individual cells within the perivascular region were identified based on their DAPI staining and assigned 1 of 5 individual phenotypes based on their shape and staining pattern. The phenotype map highlights the different phenotypes identified within the perivascular regions of this particular core. The schematic illustration (bottom) shows different potential phenotypes identified in perivascular regions based on the expression patterns of CD31, desmin, and PDGFRβ. Scale bars: 100 μm. (B and C) Quantification of CD31+ vascular coverage (microvascular density [MVD]) (B) and pericyte coverage index (microvessel pericyte coverage index [MPI]) (C) in the indicated patient groups. (D and E) Relative pericyte distribution of individual patients in the triple-negative breast cancer (TNBC) group (D) and the luminal breast cancer group (E). Black bars indicate the percentage of vessels not covered by any type of pericyte analyzed (naked vessels). (F) Quantification of the percentage of coverage of all desmin+ pericytes (PDGFRβ–desmin+ and PDGFRβ+desmin+) related to CD31+ vessels. (G) Quantification of the percentage of coverage of PDGFRβ–desmin+ pericytes related to CD31+ vessels. (H) Quantification of the percentage of coverage of PDGFRβ+desmin– pericytes related to CD31+ vessels. (I) Quantification of the ratio of PDGFRβ– desmin+ pericytes/PDGFRβ+ desmin– pericytes. TNBC, n = 26; luminal, n = 45. The data are presented as mean ± SD. Unpaired 2-tailed t test was used to determine statistical significance. **P < 0.01, ****P < 0.0001. Unless otherwise indicated, TNBC, n = 28; luminal, n = 57.

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