Molecular mechanisms of tumour invasion: regulation by calcium signals

Abstract

Intracellular calcium (Ca²⁺ ) signals are key regulators of multiple cellular functions, both healthy and physiopathological. It is therefore unsurprising that several cancers present a strong Ca²⁺ homeostasis deregulation. Among the various hallmarks of cancer disease, a particular role is played by metastasis, which has a critical impact on cancer patients' outcome. Importantly, Ca²⁺ signalling has been reported to control multiple aspects of the adaptive metastatic cancer cell behaviour, including epithelial-mesenchymal transition, cell migration, local invasion and induction of angiogenesis (see Abstract Figure). In this context Ca²⁺ signalling is considered to be a substantial intracellular tool that regulates the dynamicity and complexity of the metastatic cascade. In the present study we review the spatial and temporal organization of Ca²⁺ fluxes, as well as the molecular mechanisms involved in metastasis, analysing the key steps which regulate initial tumour spread.

Keywords: calcium channel; calcium signalling; cancer cells.

Figure 1. Epithelial‐to‐mesenchymal transition (EMT), loss of cell–cell contacts and downregulation of proteins such as E‐cadherin, claudin or occludin

EMT transition is accompanied by the changes in Ca²⁺ signals due to several factors such as growth factors, cytokines and hypoxia. The most studied Ca²⁺‐permeable channels, which are associated with EMT, are indicated.

Figure 2. Global cytosolic Ca²⁺ is generally higher at the rear (marked in red), whereas Ca²⁺ flickers are enriched near the front edge of migrating cell

The key molecular components and signalling events of the cellular migration machinery are Ca²⁺ dependent. The most studied Ca²⁺‐permeable channels, which are associated with directional migration, are indicated. ERK, extracellular signal‐regulated kinase; MAPK, mitogen‐activated protein kinase; MLCK, myosin light chain kinase; Pyk2, proline‐rich tyrosine kinase 2; ROCK, Rho‐associated protein kinase; STIM, stromal interaction molecule.

Figure 3. Ca²⁺ oscillations are required for the initiation of the invadopodia formation process, whereas Ca²⁺ influx activates the focal degradation of the extracellular matrix (ECM), in particular through upregulation of the proteolytic enzymes like matrix metalloproteinases (MMPs) and cathepsins

The most studied Ca²⁺‐permeable channels, which are associated with invasiveness, are indicated. PI3K, phosphoinositide 3‐kinase; PM, plasma membrane; PtdIns(3,4)P₂, phosphatidylinositol‐3,4‐bisphosphate. N‐WASP, neural Wiscott‐Aldrich syndrome protein; PDGF, platelet‐derived growth factor; RTK, receptor tyrosine kinase.

Figure 4. Induction of local angiogenesis by Ca²⁺ signalling remodelling

In tumour cells Ca²⁺ signals regulate the secretion of proangiogenic stimuli, like vascular endothelial growth factor (VEGF). A newly formed vessel can be differentiated into the following structures: tip – represented by the migrating edge of the vessel; stalk – mostly proliferating part of the vessel; phalanx – tightly apposed, regularly ordered ECs that provide perfusion and oxygenation; mural – functional preformed ECs. Interestingly, VEGF‐ and ATP‐mediated Ca²⁺ signals provide proangiogenic effects specifically on tumour‐derived tissue and not on healthy ECs. The most studied Ca²⁺‐permeable channels, which are associated with local angiogenesis, are indicated. NAADP, nicotinic acid adenine dinucleotide phosphate. LP, long persistent; RS, repeated spikes; NSOCE, non‐store‐operated Ca²⁺ entry.