Lauren Wilkin

Background: Colorectal cancer (CRC) is the third most common cancer and the second most deadly cancer in the United States, thus improvements in treatment are of increasing interest.¹ The current treatment for stage I and II CRC is surgical resection, but once the cancer has metastasized, indicating stage III and greater, chemotherapy is indicated.¹ The issue is that even with chemotherapy treatment, survival rates can range from 10% to 70% depending on specific tumor types.² Modifying the tumor microenvironment to increase susceptibility to chemotherapy has become an area of increasing research.³ The tumor microenvironment includes the extracellular matrix, stromal cells, blood vessels, nerves, and signaling molecules.³ Fibroblasts within the tumor microenvironment are deemed cancer-associated fibroblasts (CAFs) and promote pro-tumorigenic functions including cancer cell invasion and proliferation.^4,5 Studies have shown that these CAFs express vitamin D receptors and that higher expression of these receptors is correlated with longer survival.⁶  Targeting these receptors on the CAFs could prove beneficial in reducing their pro-tumorigenic functions.

Objective: The purpose of this review is to discuss the use of vitamin D in inhibiting pro-tumorigenic functions of CAFs as well as the potential therapeutic use of vitamin D in treating cancer.

Methods: The PubMed database was used to find current research on the pro-tumorigenic functions of CAFs as well as the use of vitamin D in inhibiting these functions. The search was conducted between the years of 2018 and 2023 using the keywords “colorectal cancer,” “cancer-associated fibroblasts,” and “vitamin D.”

Results: Vitamin D administration to fibroblasts was a potent inhibitor of collagen gel contraction, cell proliferation, and cell migration, which are pro-tumorigenic functions of CAFs.^6,7 These results corresponded with an increase in CD82 expression, which is a gene that has anti-metastatic properties.⁶ In addition, S100A4 expression was decreased, which is a gene that is a marker for fibroblast activation, thus vitamin D plays a direct role in inhibiting CAFs.⁶ Interestingly, immunohistochemical staining revealed that the proteins encoded by these genes were solely expressed in the tumor stroma, indicating that the tumor stroma, specifically the CAFs, was the direct target of vitamin D.⁶ Given these implications, vitamin D treatment in conjunction with photodynamic priming and chemotherapy in mice with pancreatic cancer was studied. The addition of vitamin D to the treatment regime allowed for better tumor control at lower chemotherapeutic doses due to its effects on the tumor microenvironment and CAFs.⁸ Double therapy of vitamin D and photodynamic priming reduced the secretion of the pro-tumorigenic chemokine CXCL12, which is also present in CRC.⁸ While this study focused on pancreatic cancer, these effects could have implications in CRC due to vitamin D’s effect on CXCL12 expression.

Conclusions: Studies show the direct effects of vitamin D on inhibiting pro-tumorigenic functions of CAFs. By reducing extracellular matrix contraction and cell proliferation and migration, vitamin D can reduce CRC growth and foster a tumor microenvironment that allows for better chemotherapeutic control. Further studies should investigate the use of vitamin D in conjunction with chemotherapy for CRC treatment.

Works Cited:

1. Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, Przybyłowicz KE. A Review of Colorectal Cancer in Terms of Epidemiology, Risk Factors, Development, Symptoms and Diagnosis. Cancers. 2021;13(9):2025. https://doi.org/10.3390/cancers13092025
2. Gaiani F, Marchesi F, Negri F, Greco L, Malesci A, de’Angelis GL, Laghi L. Heterogeneity of Colorectal Cancer Progression: Molecular Gas and Brakes. International Journal of Molecular Sciences. 2021;22(10):5246. https://doi.org/10.3390/ijms22105246
3. Sanegre S, Lucantoni F, Burgos-Panadero R, de La Cruz-Merino L, Noguera R, Álvaro Naranjo T. Integrating the Tumor Microenvironment into Cancer Therapy. Cancers. 2020;12(6):1677. https://doi.org/10.3390/cancers12061677
4. Pape J, Magdeldin T, Stamati K, et al. Cancer-associated fibroblasts mediate cancer progression and remodel the tumouroid stroma. Br J Cancer. 2020;123(7):1178-1190. doi:10.1038/s41416-020-0973-9
5. Zhu HF, Zhang XH, Gu CS, et al. Cancer-associated fibroblasts promote colorectal cancer progression by secreting CLEC3B. Cancer Biol Ther. 2019;20(7):967-978. doi:10.1080/15384047.2019.1591122
6. Ferrer-Mayorga G, Gómez-López G, Barbáchano A, et al. Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer. Gut. 2017;66(8):1449-1462. doi:10.1136/gutjnl-2015-310977
7. Ferrer-Mayorga G, Niell N, Cantero R, et al. Vitamin D and Wnt3A have additive and partially overlapping modulatory effects on gene expression and phenotype in human colon fibroblasts. Sci Rep. 2019;9(1):8085. Published 2019 May 30. doi:10.1038/s41598-019-44574-9
8. Anbil S, Pigula M, Huang HC, et al. Vitamin D Receptor Activation and Photodynamic Priming Enables Durable Low-dose Chemotherapy. Mol Cancer Ther. 2020;19(6):1308-1319. doi:10.1158/1535-7163.MCT-19-0791