The TGF-ß pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells.

TGF-ß pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-ß in cancer drug resistance. In this work, we show a specific activation of the TGF-ß pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-ßRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-ß molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-ß pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients.

HER2 status of gastric carcinoma and corresponding lymph node metastasis.

Our goal is to verify HER2 status variability between primary tumor and metastatic site. Our second intention is to identify the most reliable criteria for pathological HER2 status assessment in gastric cancer node metastases since, at present, there is not a validated standard. 3 independent pathologists evaluated HER2 immunohistochemical and gene status (for IHC 2+ cases) in 34 gastric carcinoma metastatic lymph nodes and in their corresponding primary tumors. For primary gastric cancers, we followed the current HER2 assessment guidelines and for nodal metastases, we applied two immunohistochemical scoring systems with different cut-offs. The immunohistochemical inter-pathologists mean agreement was 71.4 % (κ = 0.45); a final score for each case was defined after collegial revision. By applying the two immunohistochemical criteria, we found 2 discordant cases, which can imply different pathological management. Moreover, a significantly different HER2 status between lymph node metastasis and primary tumor was obtained in 4 cases (concordance ratio 87.5 %). None of the patients would have undergone a different therapeutic pathway despite the scoring method applied. On the other hand we also detected a subset of patients who could have their therapeutic management changed, according to the differences between HER2 status in lymph nodes metastases and primary tumor.