All tags cancer Calcium signaling in cancer

Calcium signaling in cancer

This article highlights the central role of Ca2+ signaling in cell migration and describes how this process is hijacked by cancer cells.

The ubiquitous second messenger, calcium (Ca2+), is involved with all six of the Hallmarks of Cancer described by Hanahan and Weinberg in their seminal paper published in 2000 (Hanahan & Weinberg, 2000). This article will focus on the role of Ca2+ signaling in one of these hallmarks: metastasis.


Ca2+ in cell migration

In the majority of cases it is not the primary tumor that causes death in cancer patients, but the migration, or metastasis, of cancerous cells to other tissues within the body. To undergo metastasis, cancer cells must gain the ability to migrate through the extracellular matrix (ECM) and enter the bloodstream. 

Ca2+ is a crucial regulator of cell migration, essential for cells involved with processes such as wound healing and the immune response. Cell migration depends upon control of intracellular Ca2+ concentration. This is mediated by Ca2+ entry through channels at the plasma membrane and release from intracellular stores, primarily from the endoplasmic reticulum (ER).

Ca2+ channels at the plasma membrane include voltage-gated calcium channels (VGCC), ligand-gated channels, transient receptor potential (TRP) channels and store operated calcium (SOC) channels (Prevarskaya et al., 2011). At the ER, Ca2+ is released through ryanodine (RyR) and/or inositol triphosphate (IP3R) receptor channels (Wei et al., 2012).

Migrating cells establish a Ca2+ gradient across their length.This gradient increases towards the rear and is involved in disassembly of focal adhesion proteins, leading to ‘rear-end retraction’. It is the formation and disassembly of focal adhesions, known as ‘focal adhesion turnover’, which determines how fast a cell migrates (Prevarskaya et al., 2011).

Further complexities have been uncovered including TRPM7-mediated ‘flickers’ of transiently increased cytosolic Ca2+ concentration that act as a ‘mini steering wheel’ to move the cell in particular directions (Wei et al., 2009).


Ca2+ in cell migration and cancer

Considering the central role of intracellular Ca2+ concentration in cell migration it is unsurprising that Ca2+ channels and effectors are dysregulated in various cancers (Monteith et al., 2012).  

TRP channels TRPC1, TRPC6, TRPM7, TRPM8 and TRPV6 are overexpressed in human breast ductal adenocarcinoma (Dhennin-Duthille et. al 2011) with further studies implicating TRPM7 overexpression in breast and pancreatic cancer cell migration (Meng et al., 2013 and Rybarczyk et al., 2012).

Furthermore, Ca2+ release-activated calcium modulator 1 (ORAI1) and stromal interaction molecule 1 (STIM1), both of which are mediators of store-operated Ca2+ entry through the plasma membrane are essential for migration of breast cancer cells in vitro and in mouse models (Yang et al., 2009).


The future of Ca2+ in cancer research

Dysregulation of Ca2+ signaling is clearly a significant factor in the metastasis of cancer cells. However, in comparison with the study of Ca2+ signaling in areas such as neurotoxicity and cardiovascular disease, the study of Ca2+ signaling in cancer research still remains a relatively young research area, with much still to be discovered.

Due to the ubiquitous nature of Ca2+ effectors and channels, it will be a challenge for therapeutic targeting, however 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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