Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies

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.

Epithelial–mesenchymal transition in colorectal cancer metastasis: A system review

“…This is mediated by a combination of several critical features, including relative dormancy, efficient DNA repair, high expression of multidrug-resistance-type membrane transporters and protection by a hypoxic niche environment [183]. Rectal CSCs that carry both CD44 and CD54 surface markers exhibit EMT characteristics and are resistant to both 5-fluorouracil/calcium folinate/oxaliplatin (FolFox) and cetuximab treatment, the most common regimens used for patients with advanced or metastatic rectal cancer [184]. Further, chemotherapy increases the CD44 high -CD24 low cell population and these cells have stem-cell features [185].…”

CD133 + melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: Significance for melanoma treatment

“…According to the cancer stem-like cell (CSC) hypothesis, neoplastic clones are maintained by a small fraction of cells with stem cell properties. As has been demonstrated with other tumor types, melanoma progression, resistance to chemo-and radiotherapy, and recurrence are related to the activity of a small fraction of cells termed melanoma stem-like cells (MSCs) [1][2][3]. In advanced stages of melanoma, currently available surgical and non-surgical regimens provide only limited benefits perhaps because they target tumor bulk leaving the MSCs behind [1,4,5].…”

Cancer stem cells in human digestive tract malignancies

“…Besides introduced markers listed in Table 1 Apart from in vitro studies, analyzing clinical samples revealed that CD44 could be used in combination with clinicopathological information to improve the OSCC prognosis, since its overexpression, in tumor samples and peripheral blood of OSCC patients, was correlated to poor prognosis LGR5 [152,153] EpCAM [120] BMI1 [119,218] CD24 [122,125] OCT4 [118,119] SOX2 [118,119,[149][150][151] NANOG [118,119] Colon and rectum CD44 [166,[180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198]200] CD133 [161-165, 171-178, 186-188, 232] ABCG2 [75,158,159] ALDH1 [198,[222][223][224]…”

“…Meanwhile, CRC-SCs derived from surgical specimens, xenografts, and/or cell lines were characterized as CD44 + [166,181,182], CD44 + CD24 + [183], CD44 + CD54 + [184], and CD44 + EpCAM HIGH [185] cells with defined CSC behavioral properties. Besides, CD133 + CD44 + CRC cells were radiation resistant [186] and tumorigenic [187,188] and expressed other markers such as CD166 [185,189,190], EpCAM [190], and CD29 [189].…”