How Cancer Hijacks Calcium Signaling

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.

References

• Hanahan D and Weinberg R A (2000) The Hallmarks of Cancer. Cell 100, 57-70.
• Meng X, Cai C, Wu J, Cai S, Ye C, Chen H, Yang Z, Zeng H, Shen Q and Zou F (2013) TRPM7 mediates breast cancer cell migration and invasion through the MAPK pathway. Cancer Letters 333, 96-102.
• Monteith GR, Davis FM and Roberts-Thompson SJ (2012) Calcium Channels and Pumps in Cancer: Changes and Consequences. J. Biol. Chem. 287(38), 31666-73.
• Prevarskaya N, Skryma R and Shuba S (2011) Calcium in tumour metastasis: new roles for known actors. Nat Rev Cancer 11, 609-618.
• Rybarczyk P, Gautier M, Hague F, Dhennin-Duthille I, Chatelain D, Kerr-Conte J, Pattou F, Regimbeau J, Sevestre H and Ouadid-Ahidouch H (2012) Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas
• and regulates human pancreatic cancer cell migration. Int. J. Cancer 131, 851-861
• Wei C, Wang X, Chen M, Ouyang K and Long-Sheng S (2009) Calcium Flickers Steer Cell Migration. Nature 457(7231), 901-905
• Wei C, Wang X, Zheng M and Cheng H (2012) Calcium gradients underlying cell migration. Curr Op Cell Biol 24, 254-261
• Yang S, Zhang J and Huang X (2009) Orai1 and STIM1 are Critical for Breast Tumor Cell Migration and Metastasis. Cancer Cell 15, 124-134

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