Ca2+ has a central role of signaling in cell migration. This article explains how cancer cells hijack this process.
All six Hallmarks of Cancer outlined by Hanahan and Weinberg’s seminal paper of 2000 involve calcium (Ca2+) - the ubiquitous second messenger (Hanahan & Weinberg, 2000). This article will focus on the role of Ca2+ signaling in one of these hallmarks: metastasis.
Ca2+ in Cell Migration
In most cases the primary tumor is not the cause of death in cancer patients. More often, it is the migration of cancerous cells to other tissues in the body – a process called ‘metastasis’. In order to metastasize, cancer cells need to be able to enter the bloodstream by migrating through the extracellular matrix (ECM).
Crucial for cells involved in such processes as wound healing and the immune response, cell migration is regulated by Ca2+. In order for cells to migrate, they depend upon the control of intracellular Ca2+ concentration. Ca2+ entry via channels at the plasma membrane and release from intracellular stores – primarily the endoplasmic reticulum (ER) – mediate this process.
Ligand-gated channels, voltage-gated calcium channels (VGCC), transient receptor potential (TRP) channels and store-operated calcium (SOC) channels are some of the Ca2+ channels at the plasma membrane (Prevarskaya et al., 2011). Ca2+ is released at the ER through ryanodine (RyR) and/or inositol triphosphate (IP3R) receptor channels (Wei et al., 2012).
Across their length, migrating cells establish a Ca2+ gradient which increases towards the rear. This gradient has a role in the disassembly of focal adhesion proteins, which leads to ‘rear-end retraction’. ‘Focal adhesion turnover’ is the term for the formation and disassembly of focal adhesions, and it determines the speed at which cells migrate (Prevarskaya et al., 2011).
Acting as a ‘mini steering wheel’, moving cells in particular directions, TRPM7-mediated ‘flickers’ of transiently increased cytosolic Ca2+ concentration are included among several further complexities which have been revealed (Wei et al., 2009).
Ca2+ in Cell Migration and Cancer
Considering the key role of intracellular Ca2+ concentration in cell migration it is not surprising that Ca2+ channels and effectors are dysregulated in various cancers (Monteith et al., 2012).
Such TRP channels as TRPC1, TRPC6, TRPM7, TRPM8 and TRPV6 are overexpressed in human breast ductal adenocarcinoma (Dhennin-Duthille et. al 2011). Other studies implicate that TRPM7 is overexpressed in breast and pancreatic cancer cell migration (Meng et al., 2013 and Rybarczyk et al., 2012).
Additionally, two mediators of store-operated Ca2+ entry through the plasma membrane are Ca2+ release-activated calcium modulator 1 (ORAI1) and stromal interaction molecule 1 (STIM1). These mediators are essential both for the migration of breast cancer cells in vitro, as well as in mouse models (Yang et al., 2009).
The Future of Ca2+ in Cancer Research
In the metastasis of cancer cells, it is clear that dysregulation of Ca2+ signaling is a significant factor. Yet, contrary to its more advanced position in the areas of neurotoxicity and cardiovascular disease studies, the analysis of Ca2+ signaling in cancer research remains relatively unexplored. There is a lot which is yet to be discovered.
It will be difficult for therapeutic targeting due to the ubiquitous nature of Ca2+ effectors and channels. Nevertheless, as more of the key processes of Ca2+ signaling in cancer are understood, the development of targeted tools for treatment and diagnosis will be facilitated.
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