A Complex Role for Calcium Signaling in Colorectal Cancer Development and Progression

Abstract

Clinical data suggest that many malignant cancers are associated with hypercalcemia. Hypercalcemia can facilitate the proliferation and metastasis of gastric and colon tumors, and has been considered a hallmark of end-stage disease. However, it has also been reported that dietary calcium or vitamin D supplementation could reduce the risk of many types of cancers. In particular, the intestines can absorb considerable amounts of calcium via Ca 2þ -permeable ion channels, and hypercalcemia is common in patients with colorectal cancer. Thus, this review considers the role of calcium signal-ing in the context of colorectal cancer and summarizes the functions of specific regulators of cellular calcium levels in the proliferation, invasion, metastasis, cell death, and drug resistance of colorectal cancer cells. The data reveal that even a slight upregulation of intracellular Ca 2þ signaling can facilitate the onset and progression of colorectal cancer, while continuous Ca 2þ influx and Ca 2þ overload may cause tumor cell death. This dual function of Ca 2þ signaling adds nuance to the debate over the hallmarks of colorectal cancer, and may even provide new directions and strategies for clinical interventions.

Serum calcium improved systemic inflammation marker for predicting survival outcome in rectal cancer

“…On the other side of the association with inflammation, calcium may promote cancer in other ways. First, calcium has been shown to be involved in cell differentiation and proliferation through modulating cell signaling that can commonly initiate colorectal carcinogenesis, such as APC/ β-catenin and Hedgehog pathways (34)(35)(36)(37), and it has been proposed that hypercalcemic environment may help colon adenocarcinoma cells develop (38). Second, patients with bone metastasis are well known to be hypercalcemic (39) suggesting that patients with elevated serum calcium and worse survival might have undiagnosed metastatic disease before the curative-intent surgery.…”

The downregulation of NCXs is positively correlated with the prognosis of stage II–IV colon cancer

“…Calcium overload can activate many channels and factors related to calcium ions. Studies have shown that they can promote the proliferation, invasion, metastasis, and anti-apoptosis of tumor cells in CC [ 36 , 55 ].…”

“…Since the invasion and metastasis of CC are closely related to the level of intracellular Ca 2+ [ 36 ] and NCXs are important proteins involved in the regulation of cytoplasmic Ca 2+ , it is important to observe the expression of NCXs in CC and analyze the relationship between NCXs and CC. For this purpose, we collected 111 clinical cases of stage II–IV colonic tumor tissues and their distal colonic normal tissues and then measured the expression of NCX1, NCX2, and NCX3 by quantitative polymerase chain reaction (qPCR), western blotting (WB), and immunohistochemistry (IHC).…”

Heterogeneity of Colorectal Cancer Progression: Molecular Gas and Brakes

“…Although the biochemical and the clinical behavior of calcium with regard to CRC seem contrasting, calcium signaling promotes or inhibits cancer based on the ability of the tissue environment to maintain balance of its intra- and extracellular concentrations: the increase of intracellular calcium promotes cancer progression, but once the level has reached overload, cancer cell death is favored, deteriorating cancerous tissue. Although the clinical application of such behavior is not yet available, calcium channels may present as possible drug targets to reduce tumor burden [ 175 ].…”