The function of vascular endothelial growth factor (VEGF) in cancer is not limited to angiogenesis and vascular permeability. VEGF-mediated signalling occurs in tumour cells, and this signalling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumour initiation. In addition to VEGF receptor tyrosine kinases, the neuropilins are crucial for mediating the effects of VEGF on tumour cells, primarily because of their ability to regulate the function and the trafficking of growth factor receptors and integrins. This has important implications for our understanding of tumour biology and for the development of more effective therapeutic approaches.

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We demonstrate that the alpha6beta4 integrin promotes carcinoma invasion through a preferential and localized targeting of phosphoinositide-3 OH kinase (PI3K) activity. Stable expression of alpha6beta4 increased carcinoma invasion in a PI3K-dependent manner, and transient expression of a constitutively active PI3K increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more PI3K activity than ligation of beta1 integrins, establishing specificity among integrins for PI3K activation. Alpha6beta4-regulated PI3K activity was required for the formation of lamellae, dynamic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. These studies define a mechanism by which the alpha6beta4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.

Binding between sperm and egg plasma membranes is an essential step in fertilization. Whereas fertilin, a mammalian sperm surface protein, is involved in this crucial interaction, sperm receptors on the egg plasma membrane have not been identified. Because fertilin contains a predicted integrin ligand domain, we investigated the expression and function of integrin subunits in unfertilized mouse eggs. Polymerase chain reactions detected mRNAs for alpha 5, alpha 6, alpha v, beta 1, beta 3, and beta 5. Immunofluorescence revealed alpha 6 beta 1 and alpha v beta 3 on the plasma membrane. GoH3, a function-blocking anti-alpha 6 monoclonal antibody, abolished sperm binding, but a nonfunction-blocking anti-alpha 6 monoclonal antibody, a function-blocking anti-alpha v beta 3 polyclonal antibody, and an RGD peptide had no effect. Somatic cells bound sperm avidly, but only if they expressed alpha 6 beta 1. A peptide analog of the fertilin integrin ligand domain inhibited sperm binding to eggs and alpha 6 beta 1+ cells and diminished GoH3 staining of eggs. Our results indicate a novel role for the integrin alpha 6 beta 1 as a cell-cell adhesion receptor that mediates sperm-egg binding.

SUMMARY High Gleason grade prostate carcinomas are aggressive, poorly differentiated tumors that exhibit diminished estrogen receptor β (ERβ) expression. We report that a key function of ERβ and its specific ligand 5α-androstane-3β,17β-diol (3β-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma. Stimuli (TGF-β and hypoxia) that induce an epithelial-mesenchymal transition (EMT) diminish ERβ expression, and loss of ERβ is sufficient to promote an EMT. The mechanism involves ERβ-mediated destabilization of HIF-1α and transcriptional repression of VEGF-A. The VEGF-A receptor neuropilin-1 drives the EMT by promoting Snail1 nuclear localization. Importantly, this mechanism is manifested in high Gleason grade cancers, which exhibit significantly more HIF-1α and VEGF expression, and Snail1 nuclear localization compared to low Gleason grade cancers.

We report that the activity of glycogen synthase kinase-3 (GSK-3) is necessary for the maintenance of the epithelial architecture. Pharmacological inhibition of its activity or reducing its expression using small interfering RNAs in normal breast and skin epithelial cells results in a reduction of E-cadherin expression and a more mesenchymal morphology, both of which are features associated with an epithelial–mesenchymal transition (EMT). Importantly, GSK-3 inhibition also stimulates the transcription of Snail, a repressor of E-cadherin and an inducer of the EMT. We identify NFκB as a transcription factor inhibited by GSK-3 in epithelial cells that is relevant for Snail expression. These findings indicate that epithelial cells must sustain activation of a specific kinase to impede a mesenchymal transition.

SUMMARY Inhibitor-of-Apoptosis (IAP) proteins contribute to tumor progression, but the requirements of this pathway are not understood. Here, we show that intermolecular cooperation between XIAP and survivin stimulates tumor cell invasion and promotes metastasis. This pathway is independent of IAP inhibition of cell death. Instead, a survivin-XIAP complex activates NFκB, which in turn leads to increased fibronectin gene expression, signaling by β1 integrin(s), and activation of cell motility kinases, FAK and Src. Therefore, IAPs are direct metastasis genes, and their antagonists could provide anti-metastatic therapies in cancer patients.

An epithelial-mesenchymal transition (EMT) characterizes the progression of many carcinomas and it is linked to the acquisition of an invasive phenotype. Given that the tumor microenvironment is an active participant in tumor progression, an important issue is whether a reactive stroma can modulate this process. Using a novel EMT model of colon carcinoma spheroids, we demonstrate that their transforming-growth factor-␤1 (TGF-␤)-induced EMT is accelerated dramatically by the presence of activated macrophages, and we identify tumor necrosis factor-␣ (TNF-␣) as the critical factor produced by macrophages that accelerates the EMT. A synergy of TNF-␣ and TGF-␤ signaling promotes a rapid morphological conversion of the highly organized colonic epithelium to dispersed cells with a mesenchymal phenotype, and this process is dependent on enhanced p38 MAPK activity. Moreover, exposure to TNF-␣ stimulates a rapid burst of ERK activation that results in the autocrine production of this cytokine by the tumor cells themselves. These results establish a novel role for the stroma in influencing EMT in colon carcinoma, and they identify a selective advantage to the stromal presence of infiltrating leukocytes in regulating malignant tumor progression. INTRODUCTIONMany epithelial tumors undergo an epithelial-mesenchymal transition (EMT) that facilitates their invasion. The EMT is also an essential component of embryonic development, tissue remodeling, and wound repair (reviewed in Arias, 2001;Thiery, 2002). During this transition, the epithelial phenotype, characterized by strong cell-cell junctions and polarity, is replaced by a mesenchymal phenotype, with reduced cell-cell interactions, a fibroblastic morphology and increased motility. Given the importance of the EMT in carcinoma progression, there is considerable interest in understanding the mechanisms that contribute to this complex process. Although the exact mechanisms that underlie the EMT have not been elucidated, TGF-␤ has been implicated as a key inducer of the process (Oft et al., 1998;Portella et al., 1998;Lehmann et al., 2000;Bhowmick et al., 2001a;Ellenrieder et al., 2001;Fujimoto et al., 2001). TGF-␤ stimulates proliferation of many cell types, particularly those of mesenchymal origin, and it is also a potent inhibitor of epithelial cell proliferation. Contrary to an early ascribed role as a tumor suppressor (Markowitz and Roberts, 1996), TGF-␤ has been found to be abundantly expressed in many epithelial tumors and it acts in both an autocrine manner on the tumor cells themselves and as a paracrine modulator of the stroma (reviewed in Gold, 1999;de Caestecker et al., 2000;Yue and Mulder, 2001). In colon carcinoma, TGF-␤ also acts differently depending on the differentiation stage of the tumor, in general by switching from an early inhibitor of proliferation to a stimulator of growth and invasion during tumor progression (Hsu et al., 1994).TGF-␤ has been implicated as a major factor in the EMT, but this is likely to be a "multifactorial" process. Moreover, the strom...