Epithelial-mesenchymal transition of tumour buds: A histopathological parameter with potential implication in oncological therapy of colorectal carcinoma

The traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used as a folk remedy for cancer. To elucidate the mode of action of PZH against cancer, in the present study we used a 5-FU resistant human colorectal carcinoma cell line (HCT-8/5-FU) to evaluate the effects of PZH on multidrug resistance (MDR) and epithelial-mesenchymal transition (EMT) as well as the activation of TGF-βpathway. We found that PZH dose-dependently inhibited the viability of HCT-8/5-FU cells which were insensitive to treatment of 5-FU and ADM, demonstrating the ability of PZH to overcome chemoresistance. Furthermore, PZH increased the intercellular accumulation of Rhodamine-123 and downregulated the expression of ABCG2 in HCT-8/5-FU cells. In addition, drug resistance induced the process of EMT in HCT-8 cells as evidenced by EMT-related morphological changes and alteration in the expression of EMT-regulatory factors, which however was neutralized by PZH treatment. Moreover, PZH inhibited MDR/EMT-enhanced migration and invasion capabilities of HCT-8 cells in a dose-dependent manner and suppressed MDR-induced activation of TGF-βsignaling in HCT-8/5-FU cells. Taken together, our study suggests that PZH can effectively overcome MDR and inhibit EMT in human colorectal carcinoma cells via suppression of the TGF-βpathway.

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Molecular Events in Primary and Metastatic Colorectal Carcinoma: A Review

Pathology Research International ◽

10.1155/2012/597497 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 29

Author(s):

Rani Kanthan ◽

Jenna-Lynn Senger ◽

Selliah Chandra Kanthan

Keyword(s):

Colorectal Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Cpg Island ◽

Genetic Alterations ◽

Tumour Suppressor Genes ◽

Metastatic Colorectal Carcinoma ◽

Cpg Island Methylator Phenotype ◽

Mesenchymal Transition ◽

Sequence Of Events ◽

Molecular Events

Colorectal cancer (CRC) is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a) genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP), (b) genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c) microRNA, and (d) epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT), with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript.

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