Nervous System Cancers (brain, spinal cord) fought by Vitamin D
Vitamin D and Nervous System Cancers: Protective and Therapeutic Effects
Substantial research indicates that vitamin D, particularly its active form 1,25-dihydroxyvitamin D₃ (calcitriol), plays important roles in fighting nervous system cancers through multiple mechanisms including cell cycle arrest, apoptosis induction, differentiation promotion, and suppression of tumor cell migration and invasion.
Glioblastoma and Gliomas
Vitamin D has been most extensively studied in glioblastoma (GBM), the most aggressive form of brain cancer. The active vitamin D hormone inhibits cellular proliferation and induces differentiation in central nervous system cells. Multiple in vitro studies demonstrate that calcitriol and vitamin D analogues suppress proliferation and migration in human glioma cell lines that express the vitamin D receptor (VDR).[1][2][3]
Patients with glioblastoma who have 25-hydroxyvitamin D serum levels greater than 30 ng/mL prior to chemotherapy and radiation demonstrate longer overall survival. Additionally, glioblastoma patients supplementing with vitamin D following diagnosis have been reported to have a survival advantage. Expression of VDR in glioma tumors is associated with improved survival, with higher VDR expression linked to better long-term patient outcomes.[3][1]
The mechanisms by which vitamin D fights glioblastoma include promoting cell cycle arrest in the G1 phase, inducing apoptosis, and reducing migration and invasive phenotypes. Vitamin D also suppresses glioma stem-like cells (GSCs), which are thought to be highly tumorigenic and resistant to conventional therapies. Calcitriol reduces stemness properties in GSCs and synergizes with temozolomide to eliminate some GSC tumors.[2][4]
Clinical trials are investigating vitamin D's therapeutic potential. A phase II trial reported that adjunct alfacalcidiol administration with standard surgery-radiotherapy-chemotherapy treatments induced progressive and durable tumor regression in some glioblastoma patients. Ongoing trials are evaluating high-dose calcitriol (4,000 IU daily) combined with concurrent chemoradiotherapy containing temozolomide.[5][1]
Research shows that co-administration of temozolomide and vitamin D significantly inhibited tumor progression and enhanced survival in rat glioblastoma models compared to temozolomide treatment alone. A single high-dose vitamin D₃ injection (300,000 IU) in patients with low vitamin D levels undergoing craniotomy significantly reduced length of ICU stay and hospitalization.[6][1]
Neuroblastoma
Vitamin D receptor activation attenuates cell survival in metastatic neuroblastoma. Calcipotriol, a vitamin D₃ analogue, selectively targets neuroblastoma cell lines with enhanced metastatic potential, reducing proliferation and survival via VDR signaling. The treatment reduces levels of YAP and TAZ, key Hippo pathway effectors involved in tumor growth.[7][8]
Studies show that 81% of children with high-risk neuroblastoma have low vitamin D levels (deficiency or insufficiency), with 48% categorized as deficient. However, vitamin D levels were not associated with disease status at the time of evaluation. Vitamin D analogues have demonstrated effectiveness in preclinical models, with the compound 2MbisP showing efficacy in inhibiting neuroblastoma growth without causing hypercalcemia.[9][10]
Meningioma
Preoperative serum vitamin D levels show an inverse correlation with peritumoral brain edema in meningioma patients. For each 1 ng/mL increase in serum 25-hydroxyvitamin D, edema index decreased approximately 4%. Vitamin D may be a protective factor for peritumoral brain edema through its effects on blood-brain barrier integrity.[11]
Genetic studies found that the VDR Fok-I ff genotype was significantly increased in meningioma patients (15.9%) compared to controls (2.5%), with carriers having a 6.47-fold increased risk for meningioma. This suggests VDR gene polymorphisms might affect meningioma development.[12]
Pituitary Adenomas
Female patients with prolactinoma have significantly lower 25-hydroxyvitamin D levels compared to controls, with macroadenoma patients showing significantly lower levels than microadenoma patients. Vitamin D deficiency in prolactinoma patients is associated with larger adenoma size and higher prolactin levels. In regression analysis, 25-hydroxyvitamin D level was a significant predictor of adenoma size.[13][14]
Other Nervous System Tumors
For ependymomas, which commonly develop in the spinal cord and brain ventricles, limited data exists on vitamin D's role. However, vitamin D deficiency is highly prevalent among children with solid tumors, including brain tumors, with rates ranging from 23% to 72%.[15][16][17]
Research on childhood brain tumors found complex associations with neonatal vitamin D levels that appear to vary by birth weight, suggesting involvement of insulin-like growth factor pathways. Among children with non-hematological malignancies including brain tumors, the prevalence of vitamin D deficiency (below 50 nmol/L) was 41%.[18][19][20]
Mechanisms of Action
Vitamin D exerts anti-cancer effects through multiple mechanisms:[4][21][2]
Cell cycle regulation: Promoting cell cycle arrest, particularly in G1 phase, through upregulation of p21 and p27 and downregulation of cyclin proteins[1]
Apoptosis induction: Triggering programmed cell death through caspase-dependent pathways, Ca²⁺-dependent mechanisms, and sphingomyelin breakdown[21][22]
Differentiation promotion: Inducing cancer cell differentiation, reducing stemness properties[4]
Anti-invasive effects: Suppressing migration and invasion of tumor cells[2][3]
Anti-angiogenesis: Reducing tumor blood vessel formation[23]
Immune modulation: Affecting immune cell function and tumor immune microenvironment[21]
The vitamin D receptor mediates most cellular effects, and VDR expression in tumors is generally associated with better prognosis. Upregulation of VDR appears to be an endogenous response to tumor progression.[24][3][1]
Clinical Implications
A comprehensive meta-analysis of cancer outcomes found that higher 25-hydroxyvitamin D levels were associated with better overall survival (hazard ratio 0.74) and progression-free survival (hazard ratio 0.84) across multiple cancer types. While specific nervous system cancer data within large meta-analyses is limited, the preponderance of evidence from preclinical studies, epidemiological data, and clinical trials supports vitamin D's protective and therapeutic potential.[25]
Vitamin D supplementation presents an attractive therapeutic strategy given its low cost, generally good tolerability, and multiple mechanisms of action. However, achieving optimal anti-tumor effects may require higher doses than typically used for bone health, and vitamin D analogues are being developed to maximize anti-cancer activity while minimizing hypercalcemia risk.[26][10][1]
Future well-designed randomized controlled trials are needed to definitively establish vitamin D's role in preventing and treating nervous system cancers, optimize dosing strategies, and identify which patients are most likely to benefit based on VDR expression and genetic polymorphisms.[12][25][1]
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