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.

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.

Background: CCN1 plays a vital role in pancreatic carcinogenesis with an unknown mechanism. Results: CCN1 regulates Sonic-Hedgehog in pancreatic cancer cells via integrin-Notch-signaling pathway to promote in vitro motility and in vivo tumorigenic growth. Conclusion: CCN1 is a critical regulator of Sonic-Hedgehog signaling in pancreatic cancer cells. Significance: Studies suggest a mechanism whereby CCN1 regulates carcinogenic events in the pancreas.

following resources were identified as useful starting points for the animation. The Organ Procurement and Transplant Network website (https://optn.transplant.hrsa.gov/media/2116/guidance_increased_risk_organ_offers_20170327.pdf) provides a 16-page guidance document for providers on explaining risk relating to the use of IRD organs; however the document was not written for lay audiences. We drew on this resource when creating our initial draft content, text script, and storyboards. During video development we became aware of two more resources addressing increased risk donors. The Explore Transplant & Living Donation website (exploretransplant.org) provided detailed and comprehensive information about increased-risk donor kidneys via a narrated animated video (within the 'My Transplant Coach' video series). The video is 3 minutes and 41 seconds in duration but is text and graph heavy and does not describe the option of a candidate declining a kidney without losing their position on the list. The Inform Me website provides comprehensive information about increased-risk kidneys to a lay audience (https://informme.cbits.northwestern.edu/system/app2.html) in a 25 to 45 minute program that includes print materials, motion graphics, infographics, quiz questions, and narrated videos of transplant providers or kidney transplant recipients spanning 11 to 95 seconds in duration. The transplant and referring provider videos used a recorded interview without accompanying images. Motion graphics and infographics were provided without accompanying narration and are text heavy. We drew on these resources while refining our video.

Background Transplant candidates are reluctant to accept kidneys from high Kidney Donor Profile Index (KDPI) donors. Incomplete understanding can lead to transplant delays for older transplant candidates. Patients need access to understandable information to make more informed decisions about KDPI. Methods We developed a KDPI‐specific animation with input from six stakeholder groups and conducted a one‐group pre‐post study with 60 kidney transplant candidates for feasibility and acceptability to improve participant KDPI knowledge, understanding, decisional self‐efficacy, and willingness to accept a KDPI > 85% kidney. Data were compared using McNemar's test and Wilcoxon signed‐rank test. Results Compared with pre‐animation scores, post‐animation scores were significantly higher for KDPI knowledge for the entire cohort (4.6 vs 6.1, P < .001) and across different levels of age, educational attainment, health literacy, vintage, and technology access. The frequency of positive responses increased pre‐post animation for KDPI understanding (55% vs 83%, P < .001) and decisional self‐efficacy (47% vs 75%, P < .001). However, willingness to accept KDPI > 85% kidneys (32% vs 36%, P = .83) increased by 2%. After viewing simplifyKDPI, >90% indicated positive ratings on ease of watching, understanding, and engaging. Conclusion In collaboration with stakeholders, an educational animation about KDPI was developed that was well‐received and is promising to impact knowledge.

The purpose of this study was to evaluate whether 2-methoxyestradiol (2-ME 2 ), a promising anticancer agent, modulates Barrett's esophageal adenocarcinoma (BEAC) cell growth and behavior through a cellular pathway involving β-catenin in partnership with E-cadherin, which seems to play a critical role in the induction of antitumor responses in cancer cells. We found that 2-ME 2 markedly reduced the BEAC cell proliferation through regulating apoptotic machinery such as Bcl-2 and Bax. It may nullify the aggressive behavior of the cells by reducing the migratory behavior. Expressions of β-catenin and E-cadherin and binding of these two proteins is activated in a 2-ME 2 -dependent fashion in Bic-1 cells. Moreover, overexpressions of these two proteins may be due to the stabilization of these proteins by 2-ME 2 . We found that 2-ME 2 -induced antimigratory effects are mediated through the β-catenin-E-cadherin signaling pathways. In view of these results, we determined whether 2-ME 2 reduces BEAC tumor growth. Administration of 2-ME2 significantly decreased the growth of BEAC cells xenografted on the flank of nude mice. The evidence presented points out that the effect of 2-ME 2 on β-catenin-orchestrated signal transduction plausibly plays a multifaceted functional role to inhibit the proliferation and cell migration of 2-ME 2 -treated malignant cells and it could be a potential candidate in novel treatment strategies for Barrett's esophageal adenocarcinoma. Mol Cancer Ther; 9(3); 523-34. ©2010 AACR.

Estrogen receptor-alpha (ER-α) is localized in the nuclei of approximately 3-7% of normal resting breast epithelial cells with a higher proportion in lobular cells than in ductal. This number is significantly increased in atypical ductal hyperplasia, ductal carcinoma in situ (DCIS), pure intraductal carcinoma, and intraductal carcinoma with invasive duct carcinoma. Despite having this information for last 15 years, it is still uncertain how ER-α is activated in the nuclei of breast epithelial cells. CCN5/WISP-2, a member of the CCN (Cysteine-rich61/Connective Tissue Growth Factor/Nephroblastoma overexpressed) family of growth factors, is becoming an increasingly important focus in breast cancer research. CCN5/WISP-2 is a two-faced signaling molecule and plays differently in breast carcinogenesis under different micro-environmental setups. Our previous studies have shown that the transcriptional and translational activation of the WISP-2/CCN5 gene is a characteristic of estrogen receptor positive non-invasive breast tumor cell lines. Expression of the WISP-2/CCN5 gene was virtually undetected in non-transformed mammary epithelial cells. Moreover, multiple studies suggest a fine tune between CCN5 signaling and ER-α pathways, but this has not yet been fully elucidated. The main objective of this work was to establish the effect of excessive activation of CCN5 on the ER-α signaling. To do so, we generated a tri-transgenic inducible mouse model that overexpresses CCN5 under the Doxycycline (dox) environment. After the confirmation of the conditional expression of CCN5 in a mammary-specific and dox-dependent manner, morphology as well as the status of ER-α was evaluated. We found that induced expression of CCN5 by Dox in breast epithelial cells significantly increased ER-α expression and activity along with no morphological changes. Collectively, these studies indentify CCN5 as a regulator of ER-α in breast epithelial cells in a tri-transgenic mouse model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1314. doi:10.1158/1538-7445.AM2011-1314