Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins’ Synthesis in Solid Cancers

Abstract

Cobalamin or vitamin B12 (B12) is a cofactor for methionine synthase and methylmalonyl-CoA mutase, two enzymes implicated in key pathways for cell proliferation: methylation, purine synthesis, succinylation and ATP production. Ensuring these functions in cancer cells therefore requires important cobalamin needs and its uptake through the transcobalamin II receptor (TCII-R). Thus, both the TCII-R and the cobalamin-dependent metabolic pathways constitute promising therapeutic targets to inhibit cancer development. However, the link between cobalamin and solid cancers is not limited to cellular metabolism, as it also involves the circulating transcobalamins I and II (TCI or haptocorrin and TCII) carrier proteins, encoded by TCN1 and TCN2, respectively. In this respect, elevations of B12, TCI and TCII concentrations in plasma are associated with cancer onset and relapse, and with the presence of metastases and worse prognosis. In addition, TCN1 and TCN2 overexpressions are associated with chemoresistance and a proliferative phenotype, respectively. Here we review the involvement of cobalamin and transcobalamins in cancer diagnosis and prognosis, and as potential therapeutic targets. We further detail the relationship between cobalamin-dependent metabolic pathways in cancer cells and the transcobalamins’ abundancies in plasma and tumors, to ultimately hypothesize screening and therapeutic strategies linking these aspects.

Prevalence of neoplasia and concurrent diseases in dogs and cats with hypercobalaminemia: A retrospective case–control study

“…Interestingly, immunohistochemical quantification of transcobalamin II and its surface receptor in dogs and cats with naturally occurring malignant neoplasia revealed synchronous up‐regulation of expression of both proteins, which reinforces the plausible association between neoplasia and hypercobalaminemia in companion animals 10 . In human medicine, cobalamin and transcobalamin are considered biomarkers for the diagnosis and prognosis of solid cancers and possible therapeutical targets 11 . Unfortunately, the measurement of serum cobalamin does not accurately reflect intracellular cobalamin status, nor the fraction of cobalamin bound to transcobalamin II biologically available 1,2,5 .…”

“…6 Cobalamin is a cofactor for two enzymes (methionine synthase and methylmalonyl-coenzyme A mutase) that have key roles in cell proliferation, especially in methylation processes involved with DNA-synthesis. 5,10,11 As a result,…”

“…10 In human medicine, cobalamin and transcobalamin are considered biomarkers for the diagnosis and prognosis of solid cancers and possible therapeutical targets. 11 Unfortunately, the measurement of serum cobalamin does not accurately reflect intracellular cobalamin status, nor the fraction of cobalamin bound to transcobalamin II biologically available. 1,2,5 Canine and feline assays for holotranscobalamin are yet to be developed, and markers of the intracellular concentration in cobalamin (homocysteine and methylmalonic acid) were not measured in the present study, as these assays are not readily available in the United Kingdom, although further investigation of these parameters and their association with neoplasia should be investigated.…”

“…Data on the incidence of hypercobalaminemia in dogs with neoplasia is limited, although hypercobalaminemia (defined as >733 ng/L) was observed in 22% of cases with various neoplasms in one preliminary study, and in the present study, 36% of cases with neoplasia were hypercobalaminemic 6 . Cobalamin is a cofactor for two enzymes (methionine synthase and methylmalonyl‐coenzyme A mutase) that have key roles in cell proliferation, especially in methylation processes involved with DNA‐synthesis 5,10,11 . As a result, proliferative tumors have increased requirements in cobalamin, which is transported in the bloodstream bound to transcobalamin II (holotranscobalamin).…”

Acute Myeloid Leukaemia Presenting as B12 Vitamin Deficiency When Multiple Horses Become a Zebra

“…These complications occur because of the impaired mitosis of which B12 vitamin is a cofactor [ 2 ] . In rare cases, the deficit can be observed in the context of excessive cell consumption due to high cellular turnover, as happens with neoplasms [ 3 ] . We present a unique case of pancytopenia seemingly induced by B12 vitamin deficiency – and initially corrected by supplementation – that uncovered a hidden acute myeloid leukaemia only apparent after bone marrow biopsy.…”