Elevated serum Vitamin B12 and Cancer

Elevated serum vitamin B12 has been found with certain cancers.
Vitamin B12-labelled imaging agents can be used successfully to image primary and secondary cancers
Potentially the presence or re-appearance of cancer could be monitored by measuring serum vitamin B12
Apart from vitamin B12, there is evidence of increased uptake of riboflavin, folate, and/or biotin into many cancers
Paradoxically high levels of ferritin can also be a marker of the presence of cancer
Elevated Apolipoprotein A and Apo B have been associated with some cancers

Elevated B12 and Cancer

More recently elevated B12 levels have been associated with a poorer prognosis following treatment for cancer (Geissbühler etal, 2000; Oh, etal, 2018; Aloreidi and Zamulko, 2018; Lin etal, 2010). The higher the B12, the poorer the prognosis. We have not been able to find any study where the authors have "looked at" metabolic markers that one would ascribe to functional B2 deficiency, and compared it to the elevated B12 levels in these cancer studies. Studies on gastric cancer have suggested that the cancers themselves over-produce haptocorrin (R Binder), and hence elevated serum Hc-B12 may be indicative of prognosis (Wakatsuki etal, 1989; Lee etal, 2017; Waxman etal, 1977; Kane etal, 1978; Paradinas etal, 1982; Arendt et al, 2013; 2016; Takahashi et al, 2013). Elevations of serum B12 have also been found in cats with neoplasms (Trehy etal, 2014). Extreme levels of Hc-B12 (>18,000 pg/m B12) have been found in some metastatic cancers (Carmel, 1975) and may persist for long after the cancer has been treated, potentially indicating the presence of metastases (Lacombe etal, 2021). Studies by Russell-Jones and co-workers have shown that many cancers over-express receptors involved in vitamin B12 uptake, including breast cancer. Elevated serum B12 has also been associated with an increased risk of cancer (Amado-Garzon et al, 2024; Liu et al, 2024; Haghighat et al, 2023; Matejcic et al, 2017; Kim et al, 2017; Essén et al, 2019; Sottotetti et al, 2024; Naushad et al, 2014; Gimsing et al, 1987; Pirouzpanah et al, 2014; Collins et al, 2000). Elevated serum B12 and holo-haptocorrin concentrations have been associated with increased risk of prostate cancer (Collin et al, 2010). Many cancers have been shown to over-express transcobalamin, and its presence can be a biomarker for colon cancer and prognosis (Liu et al, 2020)

Vitamin B12 has been used as a targeting agent to image various tumours in vivo

Vitamin B12-targeted Rhodamine-labelled polymers have been used to image tumour metastases (top panel BisB nuclear staining of gut wall, middle panel BisB+B12-Rho-HPMA, lower panel B12-Rho-HPMA)

Radionucleotide labelling of cat mammary Carcinoma (AdenosylCbl-b-DTPA-Tc-99m iv)

Floyd and co-workers have used 131-I-Cbl to image a mouse sarcoma

Measurement of Serum B12, what does it mean?

In order to understand the data, and in order to stop the hysteria that may result from the concept that elevated B12 may be associated with cancer, one has to firstly understand what measurement of vitamin B12 in serum actually means. Hence, Serum vitamin B12 is a measurement of circulating vitamin B12 that is bound by a vitamin B12 binding protein. There are two main binding proteins Haptocorrin and Transcobalamin. Hence serum vitamin B12 DOES NOT REPRESENT free unbound vitamin B12, it represents some form of cobalamin that is trapped in the body and is not filtered out by the kidney because it is bound to either Haptocorrin, or Transcobalamin. The incorrectly named Active B12 test, measured some form of cobalamin bound to Transcobalamin. In fact the more inactive B12 that is around the higher the values for both serum and inactive B12 are. In the case of elevated serum vitamin B12, due to the presence of cancer, the cancer cells themselves have been shown to secrete either binding protein, in an attempt to sequester vitamin B12 either from the diet, the liver or from supplementation. This the cancer will do, regardless of the amount of vitamin B12 supplemented or ingested. Logically, the lower the vitamin B12, the greater the expression of the vitamin B12 binding proteins. Since functional vitamin B12 deficiency can occur at any serum level, so too can "relatively" elevated vitamin B12. Hence the measurement of serum vitamin B12 should be done in comparison to levels before or after identification or treatment of cancer.

Folate targeting to Cancers

Several different types of cancers have been shown to have increased uptake of folate (III-In-DTPA folate imaging)

Folate imaging has been found to successfully detect metastatic cancers (Sega and Low 2008)

Biotin targeting to Cancers

Many cancers have also been found to have greatly increased uptake of biotin (Russell-Jones et al, 2002, 2004, 2008), with many have dual uptake of vitamin B12 and biotin, or folate and biotin)

Riboflavin targeting to Cancers

More recently, riboflavin has also been found to target several tumours, and there are reports of elevated Riboflavin Carrier Protein being associated with pancreatic cancer (Paragomi et al, 2023). RIboflavin seems to play a dual role in cancers, in low riboflavin there is an increased risk of some cancers (Long et al, 2021; Yu et al, 2016), possibly due to its role in maintaining the activity of MTHFR and MTRR and the methylation cycle. In a similar fashion to the elevated serum B12 in some cancers, elevated serum riboflavin has been seen in colorectal cancer (Ma et al, 2023; Xu et al, 2022), Levels of the riboflavin carrier protein (RCP) are 3 to 4 times normal in many cases of breast and other cancers (Karande et al, 2001; Darguzyte et al, 2020). Riboflavin uptake is greatly enhanced in some tumour cells (Bartmann et al, 2019). Riboflavin supplementation has been shown to increase cancer cell proliferation, invasion and migration, and inhibition of of flavin-containing enzymes arrested tumor growth (Yang et al, 2013; Ozsvari et al, 2017).

Rao and coworkers (1999) found that serum RCP levels were significantly elevated in women with breast cancer (6.06 +/- 7.27 ng/ml) as compared with control subjects [0.70 +/- 0.19 ng/ml), Elevated serum RCP of > or = 1.0 ng/ml was highly predictive of the presence of breast cancer, detecting 88% of tumors in stages I-II and 100% of tumors in stages III-IV. Significantly elevated RCP was also found in hepatacellular carcinoma (Rao et al, 2006), where mean serum RCP levels in HCC were 21.75+/-14.66ng/m, significantly higher than controls (0.73+/-0.25ng/ml).

Riboflavin has also been shown to have an inhibitory role in some cancer, with levels of serum riboflavin lower in patients with esophageal cancer (Bao et al, 2013)

Measurement of Serum riboflavin, what does it mean?

In order to understand the data, and in order to stop the hysteria that may result from the concept that elevated riboflavin may be associated with cancer, one has to firstly understand what measurement of vitamin B2 in serum actually means. Hence, Serum vitamin B2 is a measurement of circulating vitamin B2 that is either free, or is bound by a vitamin B2 binding protein. In the case of elevated serum vitamin B2, due to the presence of cancer, the cancer cells themselves have been shown to secrete a riboflavin binding protein, in an attempt to sequester vitamin B2 either from the diet, the liver or from supplementation. This the cancer will do, regardless of the amount of vitamin B2 supplemented or ingested. Logically, the lower the vitamin B2, the greater the expression of the vitamin B2 binding proteins. Since functional vitamin B2 deficiency can occur at any serum level, so too can "relatively" elevated vitamin B2. Hence the measurement of serum vitamin B2 should be done in comparison to levels before or after identification or treatment of cancer.

Associated Factors - Apolipoproteins

Elevations in Apoliproteins have been found to be associated with several cancers. ApoB, and ApoA have been shown to have potential as diagnostic markers (Zhou and Luo, 2020)

Ferritin

Ferritin is differentially over-expressed in tissues from multiple malignancies, including: hepatocellular carcinoma [46], [47], Hodgkin's lymphoma [48], breast cancer [49], [50], [51], [52], [53], and pancreatic cancer [50]

Relevance of the elevated serum markers

There is strong evidence to suggest that the treatment of various cancers could be followed by monitoring the serum markers. Potentially they could be used in the initial diagnosis. There is some debated about what to do, if you find the elevated markers, whether to supplement or not. Evidence suggests that the reason for the elevated markers was some sort of nutritional deficiency in the first. This then resulted in lower methylation and thereby poorer control of oncogene expression. Unfortunately, very, very clinicians know of the associations not do National Cancer bodies such as the Cancer Council of Australia, or the American Cancer Society. Given the strong association with these markers with breast cancer in women, it is disappointing to discover that none of the societies even mention these markers, and of course don't suggest that people track them.

Monitoring Cancer using the markers

Most of the markers outlined above can be obtained with standard blood tests, hence the serum B12, folate and Apoliprotein A and B levels are standard tests. Persons who believe that may have cancer or who have been treated for it can readily obtain this data and hence raise a precautionary alarm to request further investigation, or follow the levels following treatment to see if the rates rise.

Reference data

TBA

References

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