ABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Claudins/metabolism , Colorectal Neoplasms/metabolism , Fibroblasts/pathology , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Humans , Male , Middle Aged , Tight Junctions/metabolism , Young AdultABSTRACT
In the preliminary study reported here, 37 patients with breast cancer and 10 healthy volunteers were analyzed for soluble TNF-R p55 and two variants of IL-8 consisting of 72 and 77 amino acid residues (IL-8(72) and IL-8(77), respectively) in their blood and urine with novel ELISA test systems. The clinical/prognostic values of determining these inflammatory cytokines at different stages of the cancer process appeared to depend on the treatment course being evaluated. In contrast to expectations, it was noted that there was a stabile tendency for decreased TNF-R p55 and IL-8(72) levels in the plasma and urine of breast cancer patients as compared with levels observed with healthy controls. Moreover, patients that underwent polychemotherapy treatments were notable for significant decreases in IL-8(72) and TNF-R p55 levels in their blood plasma; these findings contrasted with significant increases in these parameters in these patients' urine. Interestingly, the IL-8(77) isoform that now appeared both in the urine and plasma of patients was not detectable before initiation of the polychemotherapy. In spite of all these findings, individual fluctuations among these parameters still do not allow us to establish, at this time, any strong correlations between these values with any particular breast cancer stage or a type of treatment. Nonetheless, while the results here are preliminary, they demonstrate that testing for TNF-R, along with IL-8 isoforms, in the blood plasma and urine could potentially present a valid means for monitoring of the overall immune and disease progress/remission status in breast cancer patients. Ongoing studies with larger patient sample sizes, as well as collecting and analyzing samples at multiple time points--to minimize the potential influence of any inherent variability in cytokine levels in humans--will hopefully allow us to specify what these preliminary results reported here suggest, i.e., the potential utility of this experimental approach for determining disease progression or efficacy of treatment in cancer patients.
