Sysel AM, Valli VE, Bauer JA. Immunohistochemical quantification of the cobalamin transport protein, cell surface receptor and Ki-67 in naturally occurring canine and feline malignant tumors and in adjacent normal tissues. Oncotarget. 2015 Feb 10;6(4):2331-48. (Winn-funded research)
The discovery and development of cancer biomarkers are increasingly under scrutiny. Individualized treatment for patients is huge in human cancer medicine currently. The type of biomarker sought as ideal would diagnose disease at an early stage, tailor therapy specific to each patient, monitor response to therapy, recognize potential therapeutic toxicities, define prognosis and monitor disease progression or recurrence.
A basic premise of this study is that cancer has a high requirement for cobalamin (Vitamin B12) as the means for enabling DNA synthesis necessary for cellular replication. Transcobalamin II transprotein (TCII) and cell surface receptor (TCII-R) are essential proteins implicated in cobalamin (Cbl) transport and uptake. The increased demand for Cbl is considered supplied by two means: 1) tumor cells produce TCII that then can scavenge, bind, transport and deliver Cbl to cells, 2) the cell surface TCII-R levels become up-regulated to import more Cbl when cells are in a proliferative mode.
With this study, the authors hypothesize that the up-regulation of TCII and TCII-R proteins in tumors will prove their future usefulness by displaying the features of an ideal biomarker for cancer and demonstrate the potential utility of Cbl-based anti-tumor therapies. They have developed a standardized, objective immunohistochemical (IHC) method to quantify the presence of TCII, TCII-R and Ki-67 (a protein marker of cellular proliferation).
The study examined archived tissue samples from three each of twelve different cancer types: 1) biliary carcinoma, 2) dermal carcinoma, 3) vaccine-associated fibrosarcoma, 4) intestinal adenocarcinoma, 5) intestinal lymphoma, 6) intestinal mast cell tumor, 7) mammary adenocarcinoma, 8) nodal lymphoma, 9) oral squamous cell carcinoma, 10) soft tissue sarcoma, 11) splenic mast cell tumor and 12) urinary bladder transitional cell carcinoma. In all cases except one (intestinal mast cell tumor not express staining for TCII-R), the feline malignant tumors stained positively. The average staining values were significantly higher than found in canine malignant tumor tissues. The feline malignant tumors with the highest degree of TCII and TCII-R staining included urinary bladder transitional cell carcinoma, oral squamous cell carcinoma, biliary carcinoma, mammary adenocarcinoma and nodal lymphoma. The tumors with the lowest staining intensity were intestinal lymphoma, intestinal adenocarcinoma, splenic mast cell tumor and soft tissue sarcoma. The most proliferative tumors were intestinal lymphoma and intestinal adenocarcinoma.
In other considerations, patients with low cobalamin levels receiving successful delivery of supplemental Cbl therapy will depend on an uptake mechanism that is not up-regulated by tumor cells. Such a mechanism has not been described at this point in time. The measurement of tumor TCII-R expression may be important in knowing the usefulness of Cbl supplementation in these patients. Positive nuclear staining for Ki-67 was exhibited in all malignant tumor tissues, an indication of active cellular proliferation. Also, the data suggests that expression of these protein biomarkers can vary both within and between tumor types which may support the increasing focus on personalized cancer treatment. (VT)
Sysel AM, Valli VE, Nagle RB, Bauer JA. Immunohistochemical quantification of the vitamin B12 transport protein (TCII), cell surface receptor (TCII-R) and Ki-67 in human tumor xenografts. Anticancer Res. 2013 Oct;33(10):4203-12.