International journal of oncology

Gemcitabine inhibits the micrometastasis of non-small cell lung cancer by targeting the EpCAM-positive circulating tumor cells via the HGF/cMET pathway.

PMID 24867356


Recurrence and metastasis are responsible for the death of non-small cell lung cancer (NSCLC) patients. Circulating tumor cells (CTCs) in the metastatic pathway have proven to be essential. This pilot study evaluated the sensitivity of gemcitabine in micrometastasis and CTCs from NSCLC patients. EpCAM-positive CTCs were detected in forty patients with NSCLC at treatment initiation and disease evaluation time-points. EpCAM-positive CTCs were defined as EpCAM-positive and CD45-negative. Total RNA was isolated from EpCAM-enriched CTCs and cytokeratin levels were detected by PCR. The HGF/cMET pathway was evaluated in CTCs from patients with different treatments and in A549 cells. The EMT-related markers were analyzed by IHC. We further explored the predictive value of baseline CTCs in patients that were receiving different treatments. The median number of CTCs in NSCLC patients was 65 CTCs/ml more than in the healthy 23?fold (median, 5.2 CTCs/ml). The mean change in cell count was significantly different for patients with gemcitabine compared to patients with non-gemcitabine treatments (-86.28 vs. -15.23/ml; P<0.05). A significant decrease was noted in the expression of cytokeratin in the CTCs of the two groups (P<0.05). The HGF/cMET pathway was inactivated in CTCs and A549 cells treated with gemcitabine, and the cell migration and invasion abilities were inhibited by gemcitabine via the HGF/cMET pathway. Furthermore, the decreased cell migration and invasion abilities may also be involved in the inhibition of the epithelial-mesenchymal transition (EMT) by gemcitabine. At a median follow-up of 36 months, the CTC count was confirmed to be a robust prognostic marker in the NSCLC population (CTCs >151, median: 15.0 months and CTCs <151, median: 32.0 months). Additionally, the survival rate in the gemcitabine group (24 months) was better than in non-gemcitabine group (21 months), suggesting a therapeutic benefit for NSCLC patient survival with the common therapy plus gemcitabine. Gemcitabine treatment decreased EpCAM-positive CTCs in NSCLC patients and inhibited EMT by the HGF/cMET pathway.