Abstract
Accumulating evidence indicates that cancer-initiating cells (CICs) are responsible for cancer initiation, relapse, and metastasis. Colorectal carcinoma (CRC) is typically classified into proximal colon, distal colon, and rectal cancer. The gradual changes in CRC molecular features within the bowel may have considerable implications in colon and rectal CICs. Unfortunately, limited information is available on CICs derived from rectal cancer, although colon CICs have been described. Here we identified rectal CICs (R-CICs) that possess differentiation potential in tumors derived from patients with rectal adenocarcinoma. The R-CICs carried both CD44 and CD54 surface markers, while R-CICs and their immediate progenies carried potential epithelial–mesenchymal transition characteristics. These R-CICs generated tumors similar to their tumor of origin when injected into immunodeficient mice, differentiated into rectal epithelial cells in vitro, and were capable of self-renewal both in vitro and in vivo. More importantly, subpopulations of R-CICs resisted both 5-fluorouracil/calcium folinate/oxaliplatin (FolFox) and cetuximab treatment, which are the most common therapeutic regimens used for patients with advanced or metastatic rectal cancer. Thus, the identification, expansion, and properties of R-CICs provide an ideal cellular model to further investigate tumor progression and determine therapeutic resistance in these patients.
Highlights
Chinese populations, rectal cancer is the most common malignant tumor of the lower digestive tract and represents 460% of tumors at all subsites of Colorectal cancer (CRC).[3]
We first enriched the cancer-initiating cell (CIC) as rectospheres from human primary rectal adenocarcinoma cells that were isolated from samples surgically removed from 30 human patients who had not received neoadjuvant chemoradiotherapy (Supplementary Table S1)
Rectal cancer cells were cultured in a serum-free medium (SFM) supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor
Summary
Rectal cancer is the most common malignant tumor of the lower digestive tract and represents 460% of tumors at all subsites of CRCs.[3]. Increasing evidence suggests that therapeutic resistance is mediated by cancer-initiating cells (CICs), which are a small subset of cancer cells that may be responsible for cancer initiation, development, and relapse.[5,6,7] Putative CIC populations have been identified in several types of solid tumors, such as brain,[8] breast cancer,[9] melanoma,[10] pancreatic adenocarcinoma,[11] lung cancer,[12] gastric adenocarcinoma,[13] and colon cancer.[6,14,15] Recently used and prominent techniques based on the expression of specific markers and functional stem cell-like properties, including high clonogenicity, differentiation capacity, spheroid formation, and the ability to reproduce xenograft tumors in immunodeficient mice, are becoming standard assays for CIC identification. Chemotherapy resistance of CICs has been described in a variety of epithelial malignancies, including colon cancer.[20]
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