Abstract
Tumors exist in a complex milieu where interaction with their associated microenvironment significantly contributes to disease progression. Cancer-associated fibroblasts (CAFs) are the primary component of the tumor microenvironment and participate in complex bidirectional communication with tumor cells. CAFs support the development of various hallmarks of cancer through diverse processes, including direct cell–cell contact, paracrine signaling, and remodeling and deposition of the extracellular matrix. Calcium signaling is a key second messenger in intra- and inter-cellular signaling pathways that contributes to cancer progression; however, the links between calcium signaling and CAFs are less well-explored. In this review, we put into context the role of calcium signaling in interactions between cancer cells and CAFs, with a focus on migration, proliferation, chemoresistance, and genetic instability.
Highlights
This review discusses the association between cancer associated fibroblasts (CAFs) and cancer cells in the context of Ca2+ signaling, as well as Ca2+ signaling in CAFs, and how these impact both cancer progression and the development of CAF properties
store-operated calcium entry (SOCE) is activated by a two-step process: first the internal endoplasmic reticulum (ER) stores are released, typically downstream of G protein-coupled receptors (GPCRs) or tyrosine kinase receptors (TKRs) activation, and this depletion of ER calcium is detected by stromal interaction molecule 1 (STIM1), which activates the ORAI1 channel, resulting in Ca2+ entry [1]
This study did not show that CAF-secreted Stromal Cell Derived Factor 1 (SDF-1) could produce this outcome and used exogenous addition of SDF-1. These findings show that (A) CAFs produce and secrete SDF-1, which promotes migration and invasion in cancer cells, and (B) SDF-1 produces a Ca2+ response that is required for the migration phenotype (Figure 1B)
Summary
Cancer is a highly heterogeneous disease and is one of the primary causes of death worldwide. Many studies and comprehensive reviews have linked calcium (Ca2+ ) signaling with cancer progression [1] and detailed the role of Ca2+ in intercellular communication, primarily in the nervous system [2,3] and in cancer [4,5]. The interplay between cancer cells and their surrounding environment, termed the tumor microenvironment (TME), and especially cancer associated fibroblasts (CAFs), has been of growing interest over the past decade. TME compartment [6,7,8], there are no reviews on Ca2+ signaling in CAFs. This review discusses the association between CAFs and cancer cells in the context of Ca2+ signaling, as well as Ca2+ signaling in CAFs, and how these impact both cancer progression and the development of CAF properties
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