BackgroundGlioblastoma multiforme (GBM, WHO grade IV) is the most common and most malignant of astrocytic brain tumors, and is associated with rapid invasion into neighboring tissue. In other tumor types it is well established that such invasion involves a complex interaction between tumor cells and locally produced extracellular matrix. In GBMs, surprisingly little is known about the associated matrix components, in particular the fibrillar proteins such as collagens that are known to play a key role in the invasion of other tumor types.Methodology/Principal FindingsIn this study we have used both the Masson's trichrome staining and a high resolution multiple immunofluorescence labeling method to demonstrate that intratumoral fibrillar collagens are an integral part of the extracellular matrix in a subset of GBMs. Correlated with this collagen deposition we observed high level expression of the collagen-binding receptor Endo180 (CD280) in the tumor cells. Further, interrogation of multiple expression array datasets identified Endo180 as one of the most highly upregulated transcripts in grade IV GBMs compared to grade III gliomas. Using promoter analysis studies we show that this increased expression is, in part, mediated via TGF-β signaling. Functionally, we demonstrate that Endo180 serves as the major collagen internalization receptor in GBM cell lines and provide the first evidence that this activity is critical for the invasion of GBM cells through fibrillar collagen matrices.Conclusions/SignificanceThis study demonstrates, for the first time, that fibrillar collagens are extensively deposited in GBMs and that the collagen internalization receptor Endo180 is both highly expressed in these tumors and that it serves to mediate the invasion of tumor cells through collagen-containing matrices. Together these data provide important insights into the mechanism of GBM invasion and identify Endo180 as a potential target to limit matrix turnover by glioma cells and thereby restrict tumor progression.

SummarySmall cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.

Blood vessel networks form in a 2-step process of sprouting angiogenesis followed by selective branch regression and stabilization of remaining vessels. Pericytes are known to function in stabilizing blood vessels, but their role in vascular sprouting and selective vessel regression is poorly understood. The endosialin (CD248) receptor is expressed by pericytes associated with newly forming but not stable quiescent vessels. In the present study, we used the Endosialin ؊/؊ mouse as a means to uncover novel roles for pericytes during the process of vascular network formation. We demonstrate in a postnatal retina model that Endosialin ؊/؊ mice have normal vascular sprouting but are defective in selective vessel regression, leading to increased vessel density. Examination of the Endosialin ؊/؊ mouse tumor vasculature revealed an equivalent phenotype, indicating that pericytes perform a hitherto unidentified function to promote vessel destabilization and regression in vivo in both physiologic and pathologic angiogenesis. Mechanistically, Endosialin ؊/؊ mice have no defect in pericyte recruitment. Rather, endosialin binding to an endothelial associated, but not a pericyte associated, basement membrane component induces endothelial cell apoptosis and detachment. The results of the present study advance our understanding of pericyte biology and pericyte/endothelial cell cooperation during vascular patterning and have implications for the design of both proand antiangiogenic therapies. (Blood. 2012;120(7):1516-1527) IntroductionThe expansion of existing blood vessels, known as angiogenesis, is a critical process that occurs in response to an insufficient supply of nutrients and oxygen during development and tissue regeneration. The deregulated generation and abnormal remodeling of blood vessels can promote the expansion of tumors or fail to restore tissue oxygenation adequately, contributing to ischemic disease progression (eg, in diabetic retinopathy). Therefore, the identification of the cellular and molecular targets for therapeutic strategies to influence vascular network formation and remodeling is of considerable clinical importance. 1,2 Angiogenesis is initiated in response to local production of proangiogenic factors, in particular VEGF-A, which promote new vascular sprout formation by the induction and migration of leading tip cells and by stimulating the proliferation of neighboring stalk cells. In addition, VEGFmediated regulation of the Delta-like 4/Notch1 signaling pathway ensures the correct spatiotemporal coordination of tip versus stalk cell specialization required for organized patterning of new vascular networks. 3 Subsequent to sprouting angiogenesis, the initial vascular plexus is remodeled extensively. Key to this remodeling is the pruning of unwanted capillaries through selective branch regression. The remaining vessels mature and are stabilized, which marks the end of vessel plasticity and reflects the quiescent state of the new hierarchical vascular network. With the exception of the complete regr...