Calcium Sensing Receptor [CaSR]

I was about to work on another alphabetical food-supplements post (on calcium), when I read a new study about a topic that I wasn't aware of: the role of the Calcium Sensing Receptor [CaSR] in PCa.

The conventional view on calcium in PCa is that it interferes with vitamin D conversion by the kidneys (calcidiol to calcitriol ... aka 25(OH)D to 1,25(OH)D) that is essential if PCa is to be treated vith vitamin D. PCa cells lose the ability to do the conversion. Thus, dairy & calcium supplements are associated with disease progression, due to local vitamin D 'deficiency'.

CaSR adds a new wrinkle to the debate.

CaSR has a role in calcium homeostasis, but is quite versatile it seems, & has a number of other roles in the body. As such, it cannot be directly targeted by a therapy.

CaSR has unusual roles in cancer:

... "loss of normal CaSR-induced response to extracellular calcium is observed in cancers of the colon and ovary, while increased release of PTHrP {parathyroid hormone} is observed in cancers of the breast {&} prostate ..." [1] Levels of CaSR are lowered in some cancers, but increased in others - such as PCa.

CaSR is thought to have a major role in metastasis to bone. Not that BCa & PCa bone metastases are similar - BCa's are largely osteolytic (destructive of bone), whereas PCa bone metastases are predominantly osteoblastic (overproduction of normal bone cells.)

Sarkar & Kumar conclude their CaSR review [1] with:

"CaSR is neither a potent oncogene nor tumor supressor, it does play an important role in Ca2+ homeostasis, which indirectly maintains a balance between proliferation and differentiation in response to change in extra cellular calcium level. Hence there should be a balanced intake of calcium rich diet, like patients suffering from colon or ovarian cancer should increase the calcium intake, while patients with prostate or breast cancer should decrease the intake of calcium rich food."

i.e. a warning to men with PCa to decrease calcium intake.

Paleolithic hunter-gatherers managed to maintain healthy bones without access to dairy products & calcium supplements, or calcium-enriched orange juice, so it should be safe to cut those things out if one eats enough greens (LOL).

In 2013, Giovannucci/Shui reported [2] that a "Common Genetic Variation of the Calcium-Sensing Receptor {was associated with} Lethal Prostate Cancer Risk". This association "was stronger in men with low 25(OH)D".

OK, that's just a reminder that vitamin D status is important.

A 2014 study [3] found that CaSR levels were hiigher in mets to bone compared to the primary tumor. The CaSR increase did not occur in mets to other tissue. Were those cells already high in CaSR & gravitated to bone, or did the increase occur after they docked?

"Stimulation of PTHrP secretion by the high level of CaSR expressed by this subpopulation of cells might enhance their capacity to establish metastases in bone. "

In the new study [4], Giovannucci/Shui are back (with outside help):

"We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009."

"On average, men were followed up 13.6 years, during which there were 83 lethal events."

"High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables {twice the risk}"

"Additionally, there was evidence of effect modification by VDR {vitamin D receptor} expression; CaSR was associated with lethal progression among men with low tumor VDR expression {risk factor = 3.2} but not in cases with high tumor VDR expression {risk factor = 0.8}"

So, once again, it seems that vitamin D status is important. Loss of the receptor (VDR) is a significant event when CaSR levels are high in a tumor cell.

In fact, Giovannucci had reported on the importance of the VDR in 2011 [5]:

"Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis .., lower Gleason score .., and less advanced tumor stage ... and were more likely to have tumors harboring the TMPRSS2:ERG fusion ..."

"Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer {83% reduced risk}."

Ideally, one needs a way to increase VDR expression in PCa. In the meantime, according to Sarkar & Kumar, it would be prudent to be in control of calcium intake.

(I wonder how easy it is to test for CaSR in bone met biopsies?)

-Patrick

[1] apocpcontrol.org/paper_file...

[2] cebp.aacrjournals.org/conte...

[3] ncbi.nlm.nih.gov/pmc/articl...

[4] ncbi.nlm.nih.gov/pubmed/271...

[5] ncbi.nlm.nih.gov/pmc/articl...

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