Role of aneuploid circulating tumor cells and CD31+ circulating tumor endothelial cells in predicting and monitoring anti-angiogenic therapy efficacy in advanced NSCLC.

Tongmei Zhang,Peter Ping Lin,Fanbin Hu,Qunhui Wang,Baolan Li,Jie Li,Lina Zhang,Yuan Gao,Ying Wang,Jinjing Tan,Olivier Gires,Hongmei Zhang,Daisy Dandan Wang,Yanxia Liu

doi:10.1002/1878-0261.13092

Abstract

Prognosticating the efficacy of anti‐angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co‐detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non‐small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell‐based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post‐therapeutic platelet endothelial cell adhesion molecule‐1 (CD31)– CTCs and CD31+ CTECs exhibited a significantly reduced median progression‐free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)+ CTECs (mesenchymal M‐type) at baseline revealed a significantly shortened mPFS compared with patients with Vim– CTECs. Post‐therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)+ CTCs and CTECs (epithelial E‐type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post‐therapeutic patients possessing de novo EpCAM+/Vim+ (hybrid E/M‐type) CTECs displayed the shortest mPFS. Patients harboring either pre‐ or post‐therapeutic EpCAM–/Vim– null CTECs (N‐type) exhibited a better response to therapy compared to patients harboring EpCAM+ and/or Vim+ CTECs. The presented results support the notion that baseline Vim+ CTECs and post‐therapeutic EpCAM+ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti‐angiogenesis combination regimens in NSCLC patients.

Highlights

Tumor neovascularization is primarily composed of endothelium-dependent angiogenesis and vasculogenesis [1]
Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
In contrast to markedly reduced overall circulating endothelial cells (ECs) in chemotherapeutic breast cancer patients at PD [48], the present study demonstrated that an upward trend in terms of a concurrent increase in a total number of post-therapeutic aneuploid circulating tumor endothelial cell (CTEC) and circulating tumor cell (CTC) in the ascending cohort significantly correlated with a shortened median PFS (mPFS) and median OS (mOS) (Fig. 4B)

Summary

Introduction

Tumor neovascularization is primarily composed of endothelium-dependent angiogenesis and vasculogenesis [1]. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is highly expressed by many carcinoma cells including lung cancer cells. In the hypoxic tumor microenvironment (TME), VEGF is secreted from neoplastic cells, followed by its binding to the VEGF receptor (VEGFR) expressed on ECs [3], thereby promoting tumor angiogenesis. Aneuploid TECs are predominately derived from the endothelialization of cancer cells and cancerization of ECs induced by hypoxia in the TME [6]. The former process consists of both trans-differentiation of tumor cells into TECs and heterotypic cell fusion of neoplastic cells with ECs [7,8]. CTECs were found to correlate with neoadjuvant chemotherapeutic efficacy in breast cancer patients [15] and immunotherapeutic resistance in lung cancer patients [17]

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