Abstract
Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by genetically deregulated cancer cells and is often associated with high tumor grade and cancer therapy resistance. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumors, and contributes also in part to metastasis. VM has been observed in ovarian cancer and in triple negative breast cancer (TNBC) and shown to correlate with decreased overall cancer patient survival. Thus, strategies designed to inhibit VM may improve cancer patient treatments. In this study, sortilin (SORT1) receptor was detected in in vitro 3D capillary-like structures formed by ES-2 ovarian cancer and MDA-MB-231 TNBC-derived cells when grown on Matrigel. SORT1 gene silencing or antibodies directed against its extracellular domain inhibited capillary-like structure formation. In vitro, VM also correlated with increased gene expression of matrix metalloproteinase-9 (MMP-9) and of the cancer stem cell marker CD133. In vivo ES-2 xenograft model showed PAS+/CD31- VM structures (staining positive for both SORT1 and CD133). TH1904, a Doxorubicin-peptide conjugate that is internalized by SORT1, significantly decreased in vitro VM at low nM concentrations. In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. TH1902, a Docetaxel-peptide conjugate, altered even more efficiently in vitro VM at pM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.
Highlights
Efficient supply of oxygen and nutrients within solid tumors was originally believed to be performed through angiogenesis, an endothelial cell (EC)-mediated process leading to new blood vessels [1]
These results indicate that SORT1 is present in ES-2 and MDA-MB-231 cancer cells that form in vitro vasculogenic mimicry (VM)
This study is the first to provide direct evidence that SORT1 is involved in the crucial molecular events required to generate VM in SORT1-positive ES-2 ovarian cancer and MDA-MB-231derived triple negative breast cancer (TNBC) cell models
Summary
Efficient supply of oxygen and nutrients within solid tumors was originally believed to be performed through angiogenesis, an endothelial cell (EC)-mediated process leading to new blood vessels [1]. Plasticity of aggressive tumors allows an alternate blood perfusion process to take place through an EC-free mechanism termed vasculogenic mimicry (VM) [2,3,4]. Such process further provides a potential dissemination route for highly aggressive and metastatic human cancers, as patterned vessel-like channel structures were reported in melanomas where red blood cells, but not EC, were detected [5, 6]. VM has been characterized in carcinomas of ovary, breast, lung, liver, colorectal, prostate, bladder, kidney, sarcomas and gliomas [4, 8], and survival analyses indicate that patients which exhibit high VM processes within their tumors had a poor clinical outcome [9]. Cancer stem cells (CSC) and epithelium-toendothelium transition, a subtype of epithelial-to-mesenchymal transition, have been reported to trigger VM by stimulating cancer cell plasticity and remodeling of the extracellular matrix (ECM) that enabled the connection of VM channels to host blood vessels [10]
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