Glioblastomas (GBMs), the most common primary brain tumor in adults, are characterized by resistance to chemotherapy and radiotherapy. One of the defining characteristics of GBM is an abundant and aberrant vasculature. The processes of vascular co-option, angiogenesis, and vasculogenesis in gliomas have been extensively described. Recently, however, it has become clear that these three processes are not the only mechanisms by which neovascularization occurs in gliomas. Furthermore, it seems that these processes interact extensively, with potential overlap among them. At least five mechanisms by which gliomas achieve neovascularization have been described: vascular co-option, angiogenesis, vasculogenesis, vascular mimicry, and (the most recently described) glioblastoma-endothelial cell transdifferentiation. We review these mechanisms in glioma neovascularization, with a particular emphasis on the roles of hypoxia and glioma stem cells in each process. Although some of these processes are well established, others have been identified only recently and will need to be further investigated for complete validation. We also review strategies to target glioma neovascularization and the development of resistance to these therapeutic strategies. Finally, we describe how these complex processes interlink and overlap. A thorough understanding of the contributing molecular processes that control the five modalities reviewed here should help resolve the treatment resistance that characterizes GBMs.

The poor prognosis of glioblastoma (GBM) routinely treated with ionizing radiation (IR) has been attributed to the relative radioresistance of glioma initiating cells (GIC). Other studies suggest that GIC are sensitive but the response is mediated by undefined factors in the microenvironment. GBM produce abundant transforming growth factor-β (TGFβ), a pleotropic cytokine that promotes effective DNA damage response. Consistent with this, radiation sensitivity, as measured by clonogenic assay, of cultured murine (GL261) and human (U251, U87MG) glioma cell lines, increased approximately 25% when treated with LY364947, a small molecule inhibitor of TGFβ type I receptor kinase, prior to irradiation. Mice bearing GL261 flank tumors treated with 1D11, a pan-isoform TGFβ neutralizing antibody, exhibited significantly increased tumor growth delay following IR. GL261 neurosphere cultures were used to evaluate GIC. LY364947 had no effect on primary or secondary neurosphere-forming capacity. IR decreased primary neurosphere formation by 28%, but did not reduce secondary neurosphere formation. In contrast, LY364947 prior to IR decreased primary neurosphere formation by 75% and secondary neurosphere formation by 68%. Notably, GL261 neurospheres produced 3.7-fold more TGFβ per cell compared to traditional culture, suggesting that TGFβ production by GIC promotes the DNA damage response and self-renewal and creates microenvironment mediated resistance. Consistent with this, LY364947 treatment in irradiated GL261 neurosphere-derived cells decreased DNA damage responses, H2AX and p53 phosphorylation, and induction of self-renewal signals, Notch1 and CXCR4. These data motivate the use of TGFβ inhibitors with radiation to improve therapeutic response in GBM patients.

Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation and differentiation along the erythroid lineage. Recent studies have shown that Epo is a pleiotropic cytokine that is proangiogenic and exerts broad tissue-protective effects in diverse nonhematopoietic organs. Recombinant Epo (rEpo) has been widely used in the clinic to prevent or treat malignancy-associated anemia. A series of clinical trials have documented the efficacy of rEpo in reducing RBC transfusion requirements and improving quality of life in cancer patients, and a recent meta-analysis suggested a positive effect on survival. However, two randomized trials reported negative outcomes with rEpo, as patients in the rEpo arm fared worse than their placebo-treated counterparts with respect to progression-free survival. The expression of Epo receptor (EpoR) in cancer cells has raised the possibility that exogenous rEpo may exert direct effects on tumor cells associated with the potential for stimulation of proliferation, inhibition of apoptosis, or modulation of sensitivity to chemoradiation therapy.The presence of an autocrine-paracrine Epo-EpoR system in tumors and potential effects of Epo on tumor microenvironment and angiogenesis are consistent with a complex biology for Epo-EpoR signaling in cancer that requires further research.This review describes Epo and EpoR biology, focusing on the pleiotropic effects of Epo on nonhematopoietic tissues as well as the expression and function of EpoR in cancer cells.

SSM and NSSM have been offered to patients with relatively low-risk breast cancer as oncologically safe while affording superior cosmesis with one-step immediate reconstruction. Our series demonstrates that either procedure can be offered to patients with more advanced cancers requiring postoperative RT. The complication rates are comparable to those reported for patients undergoing RT after traditional mastectomies.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin with a rising incidence. MCC has metastatic potential regardless the size of the primary tumor and a 5-year disease associated mortality rate is 46 %. Surgery and radiation are the mainstays of management for primary MCC. There is no evidence-based effective chemotherapy for recurrent or metastatic diseases to date. In-depth mechanistic studies in MCC have uncovered important cellular events and the association with a polyomavirus, which has provided direct evidence for molecular targeted and immunotherapy. Further perspective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of molecular targeted immunotherapy alone or in combination with chemotherapy in MCC.