Do drugs interact together in cardiovascular prevention? A meta-analysis of powerful or factorial randomized controlled trials.

AIM OF THE STUDY: To explore whether preventive cardiovascular drugs (antihypertensive, antiplatelet, lipid lowering and hypoglycemic agents) interact together in cardiovascular prevention. METHODS: We searched PubMed®, Web of science™, Embase and Cochrane library for powerful randomized placebo-controlled trials (>1000 patients). We explored whether drug effect on major vascular events changed according to cross-exposure to other drug classes or to cardiovascular risk factors (hypertension or type 2 diabetes), through a meta-analysis of relative odds ratio computed by trial subgroups. A significant interaction was suggested from confidence intervals of the ratio of odds ratios, when they excluded neutral value of 1. RESULTS: In total, 14 trials with 178,398 patients were included. No significant interaction was observed between co-prescribed drugs or between these medications and type 2 diabetes/hypertension status. CONCLUSIONS: Our meta-analysis is the first one to evaluate drug-drug and drug-hypertension/type 2 diabetes status interactions in terms of cardiovascular risks: we did not observe any significant interaction. This indirectly reinforces the rationale of using several contrasted mechanisms to address cardiovascular prevention; and allows the combination effect prediction by a simple multiplication of their odds ratios. The limited availability of data reported or obtained from authors is a strong argument in favor of data sharing.

Correction: Schwann cells support oncogenic potential of pancreatic cancer cells through TGFß signaling.

The original version of this article contained an error in the name of one of the co-authors (Kayvan Mohkam). This has been corrected in the PDF and HTML versions.

Schwann cells support oncogenic potential of pancreatic cancer cells through TGFß signaling.

Pancreatic ductal adenocarcinoma (PDAC) is one of the solid tumors with the poorest prognosis. The stroma of this tumor is abundant and composed of extracellular matrix and stromal cells (including cancer-associated fibroblasts and immune cells). Nerve fibers invading this stroma represent a hallmark of PDAC, involved in neural remodeling, which participates in neuropathic pain, cancer cell dissemination and tumor relapse after surgery. Pancreatic cancer-associated neural remodeling is regulated through functional interplays mediated by physical and molecular interactions between cancer cells, nerve cells and surrounding Schwann cells, and other stromal cells. In the present study, we show that Schwann cells (glial cells supporting peripheral neurons) can enhance aggressiveness (migration, invasion, tumorigenicity) of pancreatic cancer cells in a transforming growth factor beta (TGFß)-dependent manner. Indeed, we reveal that conditioned medium from Schwann cells contains high amounts of TGFß able to activate the TGFß-SMAD signaling pathway in cancer cells. We also observed in human PDAC samples that high levels of TGFß signaling activation were positively correlated with perineural invasion. Secretome analyses by mass spectrometry of Schwann cells and pancreatic cancer cells cultured alone or in combination highlighted the central role of TGFß in neuro-epithelial interactions, as illustrated by proteomic signatures related to cell adhesion and motility. Altogether, these results demonstrate that Schwann cells are a meaningful source of TGFß in PDAC, which plays a crucial role in the acquisition of aggressive properties by pancreatic cancer cells.

Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic Tumorigenesis.

BACKGROUND & AIMS: Transforming growth factor beta (TGFß) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFß activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFß-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. METHODS: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFß receptor (TßRICA) in the pancreatic acinar compartment. RESULTS: We observed that TßRICA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1ß, Sox9, and Hes1. CONCLUSIONS: We demonstrate that TGFß pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients.