ROS and TGFβ: from pancreatic tumour growth to metastasis

Abstract

Transforming growth factor β (TGFβ) signalling pathway switches between anti-tumorigenic function at early stages of cancer formation and pro-tumorigenic effects at later stages promoting cancer metastasis. A similar contrasting role has been uncovered for reactive oxygen species (ROS) in pancreatic tumorigenesis. Down-regulation of ROS favours premalignant tumour development, while increasing ROS level in pancreatic ductal adenocarcinoma (PDAC) enhances metastasis. Given the functional resemblance, we propose that ROS-mediated processes converge with the spatial and temporal activation of TGFβ signalling and thereby differentially impact early tumour growth versus metastatic dissemination. TGFβ signalling and ROS could extensively orchestrate cellular processes and this concerted function can be utilized by cancer cells to facilitate their malignancy. In this article, we revisit the interplay of canonical and non-canonical TGFβ signalling with ROS throughout pancreatic tumorigenesis and metastasis. We also discuss recent insight that helps to understand their conflicting effects on different stages of tumour development. These considerations open new strategies in cancer therapeutics.

Redox signaling at the crossroads of human health and disease

“… 332 ROS dynamically interact with TGF‐β, modulating EMT through multiple signaling pathways. 332 Canonical TGF‐β signaling was mediated by phosphorylated Smad2/3 proteins that entered the nucleus and activated Smad4, which activated the EMT process. In addition, noncanonical pathways mediated by RAC, 333 RAS, MAPK, 334 and TGF‐β‐activated kinase 1 335 signaling also play essential roles in ROS‐mediated EMT.…”

Cancer and Autoimmune Diseases: A Tale of Two Immunological Opposites?

“…In addition it was shown in psoriasis rat model that ROS prevent imiquimod-induced psoriatic dermatitis by enhancing Tregs function ( 40 ). On the other hand, TGFβ excreted by Treg cells induced the generation of ROS by NADPH oxidase ( 41 , 42 ). In accordance with these observations, Treg-induced immunosuppression in the tumor microenvironment is mediated by Tregs-generated ROS ( 43 ).…”

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

“…Moreover, Treg crosstalk with and are dependent on MDSCs as in a PDAC mouse model, depletion of MDSC led to a reduced recruitment and/or induction of Treg in pancreatic tumors and development/expansion of Treg seems to require a direct cell-cell interaction with MDSC [148]. Furthermore, TGF-β is not only a trigger for Treg development but also production of reactive oxygen species (ROS) by these cells contributing to oxidative stress in the TME [218].…”