Journal article Open Access

Membranous CD44v6 is upregulated as an early event in colorectal cancer: Downregulation is associated with circulating tumor cells and poor prognosis

AGAPI KATAKI; VASSILIS G. GIANNAKOULIS; ANASTASIA DERVENTZI; KONSTANTINOS PAPIRIS; EYTHIMIOS KONIARIS; MANOUSOS KONSTADOULAKIS

Previous studies have reported that CD44 variant 6 (CD44v6) and metastasis‑associated protein 1 (MTA1) are contributing factors to cancer progression. The present study aimed to evaluate the expression profiles for associations with patients' demographic data, clinicopathological characteristics, the presence of partial epithelial‑to‑mesenchymal transition (pEMT), metastatic potential based on the presence of CK20+ CEA+ CXCR4+ circulating tumor cells (CTCs) and prognosis (median follow‑up, 45 months). Thus, frozen tissue samples from 31 patients with stage I‑III colorectal cancer (CRC), 15 benign colorectal polyps and seven normal colorectal tissues were analyzed to detect membranous (m)CD44v6 and MTA1 expression via flow cytometry. The results demonstrated that the mCD44v6 and MTA1 expression profiles were significantly correlated (rs=+0.786, P<0.001). Notably, MTA1 expression was not associated with any of the clinicopathological characteristics assessed. The percentage of mCD44v6‑positive cells within tumors was higher in the right‑sided cancer lesions (P=0.014), suggesting that proximal and distal CRCs are distinct clinicopathological entities. Furthermore, downregulated mCD44v6 expression was significantly associated with the presence of CTCs (P=0.017). This association was stronger for pEMT (co‑expression of N‑ and E‑cadherin mRNAs) primary lesions (P=0.009). In addition, patients with CRC with low levels of mCD44v6 had unfavorable survival outcomes (P=0.037). Taken together, these results suggest that targeted analysis of membranous CD44v6 as opposed to membranous‑cytoplasmic expression is important in determining the prognosis of patients with CRC. Furthermore, downregulated mCD44v6 expression in malignancies presenting CTCs reinforces the importance of tumor‑stroma reciprocal influence during the metastatic process and encourages the assessment of relevant therapeutic strategies.

The present study was supported by the VISION project (strategies to strengthen scientific excellence and innovation capacity for early diagnosis of gastrointestinal cancers), which received funding from the European Union's Horizon 2020 research and innovation programme (grant no. 857381).
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