Early incorporated endothelial cells as origin of metastatic tumor vasculogenesis

Abstract

Vascularization of solid tumors is thought to occur by sprouting or intussusceptive angiogenesis, co-option of existing vessels, and vasculogenic mimicry after the onset of tumor hypoxia, when the tumor radius exceeds the oxygen diffusion distance. In contrast, here we show that individual endothelial cells that are incorporated into pre-hypoxic tumors give rise to tumor blood vessels via vasculogenesis. Small metastatic lung tumor sections obtained after tail-vein injection of a syngeneic breast cancer cell line in the nude mice were labeled with antibodies against endothelial cell markers. Immunofluorescence showed the incorporation and mixed growth of CD31-, Tie-2-, and CD105-positive endothelial cells in tumors with radii less than oxygen diffusion distance and subsequent development of blood vessels from these early-incorporated endothelial cells. This observation lays the foundation of a novel vasculogenic paradigm of tumor vascularization, where incorporation of endothelial cells and their growth among tumor cells occur before the onset of core hypoxia in lung metastatic tumors.

Melanoma Vasculogenic Mimicry Capillary-Like Structure Formation Depends on Integrin and Calcium Signaling

“…The presence of tumor cell‐lined channels provides a potential additional route by which metastases may escape from a tumor or a lymph node into the blood stream. It has been suggested that the blood vessels in the sites of metastatic growth are being formed from within the tumor utilizing occasional EC incorporated into the tumor [10]. Therefore, the first blood vessels in metastases would be composite ones formed by both tumor and an EC.…”

Contribution of cancer stem cells to tumor vasculogenic mimicry

“…VM has been detected in melanoma, breast carcinoma, prostate carcinoma, ovarian carcinoma, astrocytoma, and Ewing sarcoma, etc (Shirakawa et al, 2002;Yue and Chen, 2005;Elzarrad et al, 2009). Microarray analysis indicates that VM-positive tumor cells of aggressive melanoma displayed elevated levels of genes associated with undifferentiated embryonic-like phenotype (Hendrix et al, 2003a).…”

Endoglin is a novel endothelial cell specification gene

“…Endothelial cells (EC) are key mediators of vasculogenesis during development and angiogenesis during the pathogenesis of ischemic cardiovascular diseases and cancer (Poole et al, 2001; Landmesser et al, 2004; Willerson and Ridker, 2004; Elzarrad et al, 2009). They also play a central role in general organogenesis (Levenberg et al, 2007), making them an important tool for tissue engineering and for studying the mechanisms involved in the pathogenesis of different forms of vascular diseases, cancer and diabetes.…”