Metastatic colon cancer cell populations contain more cancer stem-like cells with a higher susceptibility to natural killer cell-mediated lysis compared with primary colon cancer cells.

Ga Rim Kim,Jae-Ho Bae,Sae-Ock Oh,Chi-Dug Kang,Ga-Hee Ha,Sun-Hee Kim

doi:10.3892/ol.2015.2918

Abstract

In the present study, the soft agar clonogenicity and the susceptibility of clonogenic cancer cells to natural killer (NK) cells were compared between primary colon cancer cells (KM12C) and metastatic colon cancer cells (KM12L4a and KM12SM) to determine whether the metastatic cancer cells consisted of more cancer stem-like cells and were resistant to NK cell-mediated lysis. The majority of colon cancer cells were positive for putative cancer stem cell markers, including CD44, CD133 and EpCAM, with the exception of KM12C cells, of which only ~55% were positive for CD133. In addition, the expression levels of sex determining region Y-box 2, Nanog and octamer-binding transcription factor 4, which are essential for maintaining self-renewal, were higher in KM12L4a and KM12SM compared with that in KM12C cells. Consistently, an increased clonogenicity of KM12L4a and KM12SM compared with KM12C cells in soft agar was observed. The expression levels of NKG2D ligands, including major histocompatibility complex class I polypeptide-related sequence A/B and UL16 binding protein 2, and of death receptor 5 were significantly higher in KM12L4a and KM12SM than in KM12C cells. Furthermore, the results indicated an increased susceptibility of KM12L4a and KM12SM to NK cell-mediated cytotoxicity in comparison with KM12C cells. These results indicated that metastatic colon cancer cell populations may consist of more cancer stem-like cells, and have greater susceptibility to NK cell-mediated lysis compared with that of primary colon cancers.

Highlights

Whilst patients with a well‐confined primary tumor may be treated by surgical removal of the tumor, metastatic diseases are frequently incurable, and are the primary cause of cancer morbidity and mortality [1,2]
A high proportion of KM12C cells were positive for CD44 and EpCAM, CD133 expression was only detected in ~55% of these cells
As Cancer stem cells (CSCs) are thought to be responsible for metastasis and therapy‐resistance [4], the current study investigated the levels of CSC markers, the clonogenicity in soft agar and the susceptibility to natural killer (NK) cells of metastatic colon cancer cells, including the primary KM12C cell line and the highly metastatic sublines, KM12SM and KM12L4A, which have previously been shown to be resistant to anticancer drugs and ionizing radiation [21]

Summary

Introduction

Whilst patients with a well‐confined primary tumor may be treated by surgical removal of the tumor, metastatic diseases are frequently incurable, and are the primary cause of cancer morbidity and mortality [1,2]. Colorectal cancer is one of the major causes of cancer-related mortality worldwide, despite various combinations of current treatments, including surgery, chemotherapy, and/or radiation. This failure is primarily due to the resistance to existing anticancer therapies for metastatic tumor cells, which may be originate from cancer stem cells [3]. Cancer stem cells (CSCs) are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance [4]. It has been demonstrated that tumor cells with resistance to apoptosis are more likely to successfully establish metastases [6,7], and the resistance to apoptosis is increased during metastatic dissemination of colon cancer [8]. Highly metastatic tumors may comprise a greater proportion of CSCs compared with primary tumors

Methods

Results

Conclusion