Over-Expression of ßII-Tubulin and Especially Its Localization in Cell Nuclei Correlates with Poorer Outcomes in Colorectal Cancer.

Tubulin is a heterodimer of α and ß subunits, both existing as isotypes differing in amino acid sequence encoded by different genes. Specific isotypes of tubulin have associations with cancer that are not well understood. Previous studies found that ßII-tubulin is expressed in a number of transformed cells and that this isotype is found in cell nuclei in non-microtubule form. The association of ßII expression and its nuclear localization with cancer progression has not previously been addressed. We here used a monoclonal antibody to ßII to examine patients with colorectal cancer and found that patients whose tumors over-express ßII have a greatly decreased life expectancy which is even shorter in those patients with nuclear ßII. Our results suggest that ßII-tubulin may facilitate cancer growth and metastasis and, to accomplish this, may not need to be in microtubule form. Furthermore, ßII expression and localization could be a useful prognostic marker. We also found that ßII appears in the nuclei of otherwise normal cells adjacent to the tumor. It is possible therefore that cancer cells expressing ßII influence nearby cells to do the same and to localize ßII in their nuclei by an as yet uncharacterized regulatory pathway.

Treatment-related survival associations of claudin-2 expression in fibroblasts of colorectal cancer.

Claudin-2 is a trans-membrane protein-component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi-quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer-associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression-free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU±irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients.