Kim Jiha, de Sampaio Pedro Correa, Lundy Donna Marie, Peng Qian, Evans Kurt W, Sugimoto Hikaru, Gagea Mihai, Kienast Yvonne, Amaral Nayra Soares do, Rocha Rafael Malagoli, Eikesdal Hans Petter, Lønning Per Eystein, Meric-Bernstam Funda, LeBleu Valerie S
Department of Cancer Biology.
Department of Investigational Cancer Therapeutics, and.
JCI Insight. 2016 Dec 22;1(21):e90733. doi: 10.1172/jci.insight.90733.
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.
血管生成和适应性血管重塑是实体瘤生长的先决条件。血管异质性，尤其是血管周围成分，可能在决定癌症进展速度方面发挥关键作用。血管周细胞异质性对癌症进展和治疗反应的影响尚不清楚。在此，我们表明血管生成素-2（Ang2）协调乳腺癌中的周细胞异质性，对转移性疾病和化疗反应产生影响。通过对人类乳腺肿瘤标本进行多光谱成像，我们报告称，由血小板衍生生长因子受体β（PDGFRβ）和结蛋白周细胞的比例所定义的血管周围成分，提供了有关对表柔比星而非紫杉醇反应的信息。使用17种不同的患者来源的乳腺癌异种移植模型，我们证明癌细胞对基质Ang2产生有影响，并对肿瘤血管系统和血管周围异质性有癌细胞定义的控制作用。因此，肿瘤的侵袭性特征及其对治疗的不同反应可能是由癌细胞定义的不同且异质的血管生成程序的参与而产生的。
