Solid tumors require new blood vessels for growth and metastasis, yet the biology of tumor-specific endothelial cells is poorly understood. We have isolated tumor endothelial cells from mice that spontaneously develop prostate tumors. Clonal populations of tumor endothelial cells expressed hematopoietic and mesenchymal stem cell markers and differentiated to form cartilage- and bone-like tissues. Chondrogenic differentiation was accompanied by an upregulation of cartilage-specific col2a1 and sox9, whereas osteocalcin and the metastasis marker osteopontin were upregulated during osteogenic differentiation. In human and mouse prostate tumors, ectopic vascular calcification was predominately luminal and colocalized with the endothelial marker CD31. Thus, prostate tumor endothelial cells are atypically multipotent and can undergo a mesenchymal-like transition.

Cancer Cell, Vol 14, 201-211, 09 September 2008

Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.

Cancer Cell, Volume 14, Issue 3, 9 September 2008, Pages 263-273

Purhonen et al. (1) have refuted the data published in >50 reports (2, 3), neglecting to quote key articles or utilize relevant models, and have drawn unsubstantiated conclusions about the contribution of endothelial progenitor cells (EPCs) to tumor angiogenesis that are not supported by their nonquantitative data and superficially executed experiments. Their study (1) is flawed in experimental design and data interpretation. For example, they do not cite their own publication demonstrating the existence of VEGFR2+ EPCs (4) and neglect mentioning clinical validation (5, 6) and acknowledging mouse genetic models (2, 3), which provide convincing evidence for functional incorporation of EPCs into neovessels. Every figure lacks stereoconfocal-microscopic quantification of vessels that are presented as poorly defined longitudinal–linear streaks. Plasma VEGF-A levels were not measured in vivo in mice treated with VEGF-A, questioning their low level of VEGFR2+ EPC detection (3). Indeed, their FACS analysis is inaccurate because of (i) unconvincing CD31/VE-cadherin/VEGFR2 expression detected on MS-1 endothelium used as positive control and (ii) failure to show long-term marrow engraftment of donor-derived hematopoietic and authentic VEGFR2+LacZ+ colony-forming EPCs. APCmin mice develop only obstructive adenomas, rather than adenocarcinomas; therefore, it is an inappropriate model to study EPC incorporation, as Spring et al. (7) (not quoted) demonstrate that EPCs do not contribute to adenomas but contribute only to carcinomas/metastatic tumors. In the parabiotic model, wild-type EPCs compete with GPF+ EPCs, which underestimates EPC recruitment. Finally, study of 6-month-old VEGF-A-loaded Matrigel plugs in mice is impossible because Matrigel plugs are degraded within 2 months, particularly when VEGF-A by itself does not induce neoangiogenesis. No quantification of patent vessels in Matrigel plugs was provided. This article fails to disprove the established role of EPCs in supporting neoangiogenesis in certain tumors (3, 5) and metastatic transition (2)

PNAS 2008 105:E54; published ahead of print August 20, 2008, doi:10.1073/pnas.0804876105