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

Fan CW, Chen T, Shang YN, Gu YZ, Zhang SL, Lu R, OuYang SR, Zhou X, Li Y, Meng WT, Hu JK, Lu Y, Sun XF, Bu H, Zhou ZG, Mo XM - Cell Death Dis (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Digestive Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China [2] Medical Center of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, People's Republic of China [3] Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

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.

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CD44+CD54+ R-CICs resist FolFox and cetuximab therapy in vivo. (a) The definition of CD44+CD54+ and CD44+CD54− cellular populations in rectospheroids and the resultant purity after cell sorting. (b) Treatment of tumor-bearing mice generated from CD44+CD54+ R-CICs, CD44+CD54−, and caco-2 cells with cetuximab, FolFox, and cetuximab plus FolFox in vivo. Data are mean tumor size±S.D. of five tumors per group derived from two independent experiments from different patients. (#P<0.01, CD44+CD54− compared with its control; **P<0.01, *P<0.05; Caco2 cells compared with its control). (c) Survival of tumor-bearing mice derived from CD44+CD54+ R-CICs (P=0.684, cetuximab; P=0.824, FolFox; P=0.207, FolFox–cetuximab), CD44+CD54− (P=0.019, cetuximab; P=0.001, FolFox; P=0.067, FolFox–cetuximab), and caco-2 cells (P=0.003, cetuximab; P=0.003, FolFox; P=0.003, FolFox–cetuximab) treated with different regimens
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fig6: CD44+CD54+ R-CICs resist FolFox and cetuximab therapy in vivo. (a) The definition of CD44+CD54+ and CD44+CD54− cellular populations in rectospheroids and the resultant purity after cell sorting. (b) Treatment of tumor-bearing mice generated from CD44+CD54+ R-CICs, CD44+CD54−, and caco-2 cells with cetuximab, FolFox, and cetuximab plus FolFox in vivo. Data are mean tumor size±S.D. of five tumors per group derived from two independent experiments from different patients. (#P<0.01, CD44+CD54− compared with its control; **P<0.01, *P<0.05; Caco2 cells compared with its control). (c) Survival of tumor-bearing mice derived from CD44+CD54+ R-CICs (P=0.684, cetuximab; P=0.824, FolFox; P=0.207, FolFox–cetuximab), CD44+CD54− (P=0.019, cetuximab; P=0.001, FolFox; P=0.067, FolFox–cetuximab), and caco-2 cells (P=0.003, cetuximab; P=0.003, FolFox; P=0.003, FolFox–cetuximab) treated with different regimens

Mentions: To further investigate the effect of cetuximab, 5-fluorouracil/calcium folinate/oxaliplatin (FolFox), or FolFox–cetuximab on R-CICs, mice were transplanted with tumors derived from R-CICs, CD44+CD54− cells, or caco-2 cells and then treated with the indicated agents (Figure 6a). When the xenotransplanted tumors reached 0.2 cm3 in diameter, the chemotherapeutic agents were injected into the mice. The results showed that the tumor growth rate derived from CD44+CD54+ R-CICs did not show a statistical difference in the different treatment groups relative to control, while CD44+CD54− and caco-2 cells generated tumors at a significantly slower rate compared with control in different regimen (Figure 6b). The survival curves of mice derived from treatment and control groups showed that all mice carrying tumors generated from CD44+CD54+ R-CICs were not statistically different from controls and were killed within 120 days in all the regimens (Figure 6c and Supplementary Table S2). Nevertheless, cetuximab, FolFox, and FolFox–cetuximab regimens did significantly increase the overall survival of xenografts derived from CD44+CD54− and Caco-2 cells compared with control mice (Figure 6c and Supplementary Table S2). Interestingly, either in group CD44+CD54+ or CD44+CD54−, the shortest overall survival occurred in the group treated with FolFox–cetuximab compared with FolFox or cetuximab regimens alone (Supplementary Table S2).


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

Fan CW, Chen T, Shang YN, Gu YZ, Zhang SL, Lu R, OuYang SR, Zhou X, Li Y, Meng WT, Hu JK, Lu Y, Sun XF, Bu H, Zhou ZG, Mo XM - Cell Death Dis (2013)

CD44+CD54+ R-CICs resist FolFox and cetuximab therapy in vivo. (a) The definition of CD44+CD54+ and CD44+CD54− cellular populations in rectospheroids and the resultant purity after cell sorting. (b) Treatment of tumor-bearing mice generated from CD44+CD54+ R-CICs, CD44+CD54−, and caco-2 cells with cetuximab, FolFox, and cetuximab plus FolFox in vivo. Data are mean tumor size±S.D. of five tumors per group derived from two independent experiments from different patients. (#P<0.01, CD44+CD54− compared with its control; **P<0.01, *P<0.05; Caco2 cells compared with its control). (c) Survival of tumor-bearing mice derived from CD44+CD54+ R-CICs (P=0.684, cetuximab; P=0.824, FolFox; P=0.207, FolFox–cetuximab), CD44+CD54− (P=0.019, cetuximab; P=0.001, FolFox; P=0.067, FolFox–cetuximab), and caco-2 cells (P=0.003, cetuximab; P=0.003, FolFox; P=0.003, FolFox–cetuximab) treated with different regimens
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fig6: CD44+CD54+ R-CICs resist FolFox and cetuximab therapy in vivo. (a) The definition of CD44+CD54+ and CD44+CD54− cellular populations in rectospheroids and the resultant purity after cell sorting. (b) Treatment of tumor-bearing mice generated from CD44+CD54+ R-CICs, CD44+CD54−, and caco-2 cells with cetuximab, FolFox, and cetuximab plus FolFox in vivo. Data are mean tumor size±S.D. of five tumors per group derived from two independent experiments from different patients. (#P<0.01, CD44+CD54− compared with its control; **P<0.01, *P<0.05; Caco2 cells compared with its control). (c) Survival of tumor-bearing mice derived from CD44+CD54+ R-CICs (P=0.684, cetuximab; P=0.824, FolFox; P=0.207, FolFox–cetuximab), CD44+CD54− (P=0.019, cetuximab; P=0.001, FolFox; P=0.067, FolFox–cetuximab), and caco-2 cells (P=0.003, cetuximab; P=0.003, FolFox; P=0.003, FolFox–cetuximab) treated with different regimens
Mentions: To further investigate the effect of cetuximab, 5-fluorouracil/calcium folinate/oxaliplatin (FolFox), or FolFox–cetuximab on R-CICs, mice were transplanted with tumors derived from R-CICs, CD44+CD54− cells, or caco-2 cells and then treated with the indicated agents (Figure 6a). When the xenotransplanted tumors reached 0.2 cm3 in diameter, the chemotherapeutic agents were injected into the mice. The results showed that the tumor growth rate derived from CD44+CD54+ R-CICs did not show a statistical difference in the different treatment groups relative to control, while CD44+CD54− and caco-2 cells generated tumors at a significantly slower rate compared with control in different regimen (Figure 6b). The survival curves of mice derived from treatment and control groups showed that all mice carrying tumors generated from CD44+CD54+ R-CICs were not statistically different from controls and were killed within 120 days in all the regimens (Figure 6c and Supplementary Table S2). Nevertheless, cetuximab, FolFox, and FolFox–cetuximab regimens did significantly increase the overall survival of xenografts derived from CD44+CD54− and Caco-2 cells compared with control mice (Figure 6c and Supplementary Table S2). Interestingly, either in group CD44+CD54+ or CD44+CD54−, the shortest overall survival occurred in the group treated with FolFox–cetuximab compared with FolFox or cetuximab regimens alone (Supplementary Table S2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Digestive Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China [2] Medical Center of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, People's Republic of China [3] Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

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.

Show MeSH
Related in: MedlinePlus