The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Abstract

Folate receptor a (FRa) is a membrane-bound protein with high affinity for binding and transporting physiologic levels of folate into cells. Folate is a basic component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis, an observation supported by the widespread use of antifolates in cancer chemotherapy. FRa levels are high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade, raising questions of its role in tumor etiology and progression. It has been suggested that FRa might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. Indeed, cell culture studies show that expression of the FRa gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations. Whether FRa in tumors decreases in vivo among individuals who are folate sufficient, or whether the tumor's machinery sustains FRa levels to meet the increased folate demands of the tumor, has not been studied. Consequently, the significance of carrying a FRa-positive tumor in the era of folic acid fortification and widespread vitamin supplement use in countries such as Canada and the United States is unknown. Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of environmental and genetic influences on FOLR1 expression in tumor etiology and progression. This review summarizes the literature on the complex nature of FOLR1 gene regulation and expression, and suggests future research directions. ' 2006 Wiley-Liss, Inc.

The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy

“…It is therefore evident that the difference in sensitivity to pemetrexed in cell lines is not due to the presence of FRa and the uptake of pemetrexed into the cells through FRa. A review on FRa (Kelemen, 2006) suggests that further research into the presence of FRa in tumours is necessary, as there is a lack of clinical studies using tumour samples, particularly in the context of pemetrexed trials. Until recently, there has been no antibody available to detect FRa by immunohistochemistry in paraffin-embedded tumour samples, although the antibodies Mov18 and Mov19 could be used on frozen sections (Bueno et al, 2001).…”

Association of folate transporter SLC19A1 polymorphisms with the outcome of multiple myeloma after chemotherapy and tandem autologous transplantation

“…5 CK2 activity is elevated in many kinds of tumors. 6,7 Very specific inhibitors of CK2 have been developed. In previous experiments, we showed that one of these inhibitors, 4,5,6,7-tetrabromobenzimidazole (TBB), inhibited the growth of malignant pre-B lymphoblastic leukemia cells that express Bcr/ Abl P190.…”

“…DMAT has the lowest K(i) value of all known CK2 inhibitors, and is cell permeable. 8 Based on reported ranges of efficacy, 7,8 DMAT was tested at 5, 10 and 20 mM. We used the previously described PLC1 cell line, which was established from a P190 Bcr/Abl transgenic mouse that developed pro/pre-B lymphoblastic leukemia/lymphoma.…”

“…In fact, rapidly dividing cancer cells have an increased folate requirement for maintaining DNA synthesis. 7 Finally, folate involvement in MM has also been observed in a study on a specific polymorphism of 5,10-ámethylenetetrahydrofolate-reductase (MTHFR), responsible for folate metabolism and promoting DNA methylation. In particular, p16 hypermethylation, seemed to play a role in pathogenesis of myeloma and, for some authors, in overall survival.…”

Risk management of nutritional supplements in chronic illness: the implications for the care of cancer and depression

“…Effect may be dose dependent (23) Potential stimulation of bone marrow (52) › Risk of cancer-cell stimulation in dose higher than RDA (53) Theoretically, partial reversal of antifolate therapy, e.g. Methotrexate (56) Inositol Evidence inconsistent (29) .…”