BackgroundDespite recent advances in outlining the mechanisms involved in pancreatic carcinogenesis, precise molecular pathways and cellular lineage specification remains incompletely understood.ResultsWe show here that Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. Cyr61/CCN1 expression was also detected in different pancreatic cancer cell lines. The aggressive cell lines, in which the expressions of mesenchymal/stem cell molecular markers are predominant; exhibit more Cyr61/CCN1 expression. Cyr61 expression is exorbitantly higher in cancer stem/tumor initiating Panc-1-side-population (SP) cells. Upon Cyr61/CCN1 silencing, the aggressive behaviors are reduced by obliterating interlinking pathobiological events such as reversing the EMT, blocking the expression of stem-cell-like traits and inhibiting migration. In contrast, addition of Cyr61 protein in culture medium augments EMT and stemness features in relatively less aggressive BxPC3 pancreatic cancer cells. Using a xenograft model we demonstrated that cyr61/CCN1 silencing in Panc-1-SP cells reverses the stemness features and tumor initiating potency of these cells. Moreover, our results imply a miRNA-based mechanism for the regulation of aggressive behaviors of pancreatic cancer cells by Cyr61/CCN1.ConclusionsIn conclusion, the discovery of the involvement of Cyr61/CCN1 in pancreatic carcinogenesis may represent an important marker for PDAC and suggests Cyr61/CCN1 can be a potential cancer therapeutic target.

Although previous in vitro studies predicted that CCN5/ WISP-2 may act as an anti-invasive gene in breast cancer, the distribution pattern of CCN5 in breast cancer samples is conflicting. Thus, we systematically investigated the CCN5 expression profile in noninvasive and invasive breast tumor samples and its functional relevance in breast cancer progression. The studies showed that CCN5 expression is biphasic, such that in normal samples CCN5 expression is undetectable, whereas its expression is markedly increased in noninvasive breast lesions, including atypical ductal hyperplasia and ductal carcinoma in situ. Further, CCN5 mRNA and protein levels are significantly reduced as the cancer progresses from a noninvasive to invasive type. Additionally, we showed that CCN5 mRNA and protein level was almost undetectable in poorly differentiated cancers compared with the moderately or well-differentiated samples and its expression inversely correlated with lymph node positivity. The result was further supported by evaluating the RNA expression profile in microdissected sections using real-time PCR analysis. Therefore, our data suggest a protective function of CCN5 in noninvasive breast tumor cells. This hypothesis was further supported by our in vitro studies illuminating that CCN5 is a negative regulator of migration and invasion of breast cancer cells, and these events could be regulated by CCN5 through the modulation of the expression of genes essential for an invasive front. These include Snail-E-cadherin signaling and matrix metalloproteinase (MMP)-9 and MMP-2. Collectively, these studies suggest that the protective effect of CCN5 in breast cancer progression may have important therapeutic implications. [Cancer Res 2008;68(18):7606-12]

Crocetin, a carotenoid compound derived from saffron, has long been used as a traditional ancient medicine against different human diseases including cancer. The aim of the series of experiments was to systematically determine whether crocetin significantly affects pancreatic cancer growth both in vitro and/or in vivo. For the in vitro studies, first, MIA-PaCa-2 cells were treated with crocetin and in these sets of experiments, a proliferation assay using H 3 -thymidine incorporation and flow cytometric analysis suggested that crocetin inhibited proliferation. Next, cell cycle proteins were investigated. Cdc-2, Cdc-25C, Cyclin-B1, and epidermal growth factor receptor were altered significantly by crocetin. To further confirm the findings of inhibition of proliferation, H 3 -thymidine incorporation in BxPC-3, Capan-1, and ASPC-1 pancreatic cancer cells was also significantly inhibited by crocetin treatment. For the in vivo studies, MIA-PaCa-2 as highly aggressive cells than other pancreatic cancer cells used in this study were injected into the right hind leg of the athymic nude mice and crocetin was given orally after the development of a palpable tumor. The in vivo results showed significant regression in tumor growth with inhibition of proliferation as determined by proliferating cell nuclear antigen and epidermal growth factor receptor expression in the crocetin-treated animals compared with the controls. Both the in vitro pancreatic cancer cells and in vivo athymic nude mice tumor, apoptosis was significantly stimulated as indicated by Bax/Bcl-2 ratio. This study indicates that crocetin has a significant antitumorigenic effect in both in vitro and in vivo on pancreatic cancer. [Mol Cancer Ther 2009;8(2):315 -23]

Motility of vascular smooth muscle cells (SMCs) is an essential step for both normal and pathologic angiogenesis. We report here that breast tumor cells, such as MCF-7 and MDA-MB-231, can modulate this SMC migration. We present evidence that the tumor cell-derived platelet-derived growth factor (PDGF) is the key regulator of vascular SMCs motility induced by breast cancer cells. PDGF significantly upregulates neuropilin-1 (NRP-1) mRNA expression and protein production in aortic smooth muscle cells (AOSMCs) and depletion of NRP-1 production by AOSMCs with specific short hairpin RNA (shRNA) prevents the PDGF-dependent migration of vascular SMCs. Moreover, we demonstrate that PDGF physically interacts with NRP-1. We propose that tumor-derived PDGF and NRP-1 of AOSMCs function as a relay system that promotes motility of vascular SMCs.

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Background: Because CCN5 is an anti-invasive gene, present studies were designed to determine whether CCN5 exerts its anti-invasive function through controlling microRNA-10b expression. Results: Up-regulation of TWIST1, a miR-10b activator, can be achieved by CCN5 silencing through the activation of HIF-1␣ JNK signaling. Conclusion: CCN5 is a negative regulator of miR-10b in breast cancer cells. Significance: The reactivation of CCN5 could be a unique therapeutic strategy for Triple negative breast cancer.

BackgroundNew blood vessel formation, or angiogenic switch, is an essential event in the development of solid tumors and their metastatic growth. Tumor blood vessel formation and remodeling is a complex and multi-step processes. The differentiation and recruitment of mural cells including vascular smooth muscle cells and pericytes are essential steps in tumor angiogenesis. However, the role of tumor cells in differentiation and recruitment of mural cells has not yet been fully elucidated. This study focuses on the role of human tumor cells in governing the differentiation of mouse mesenchymal stem cells (MSCs) to pericytes and their recruitment in the tumor angiogenesis process.ResultsWe show that C3H/10T1/2 mouse embryonic mesenchymal stem cells, under the influence of different tumor cell-derived conditioned media, differentiate into mature pericytes. These differentiated pericytes, in turn, are recruited to bind with capillary-like networks formed by endothelial cells on the matrigel under in vitro conditions and recruited to bind with blood vessels on gel-foam under in vivo conditions. The degree of recruitment of pericytes into in vitro neo-angiogenesis is tumor cell phenotype specific. Interestingly, invasive cells recruit less pericytes as compared to non-invasive cells. We identified tumor cell-secreted platelet-derived growth factor-B (PDGF-B) as a crucial factor controlling the differentiation and recruitment processes through an interaction with neuropilin-1 (NRP-1) in mesenchymal stem cells.ConclusionThese new insights into the roles of tumor cell-secreted PDGF-B-NRP-1 signaling in MSCs-fate determination may help to develop new antiangiogenic strategies to prevent the tumor growth and metastasis and result in more effective cancer therapies.