title: A tissue-engineered subcutaneous pancreatic cancer model for antitumor drug evaluation.
abstract: The traditional xenograft subcutaneous pancreatic cancer model is notorious for its low incidence of tumor formation, inconsistent results for the chemotherapeutic effects of drug molecules of interest, and a poor predictive capability for the clinical efficacy of novel drugs. These drawbacks are attributed to a variety of factors, including inoculation of heterogeneous tumor cells from patients with different pathological histories, and use of poorly defined Matrigel(®). In this study, we aimed to tissue-engineer a pancreatic cancer model that could readily cultivate a pancreatic tumor derived from highly homogenous CD24(+)CD44(+) pancreatic cancer stem cells delivered by a well defined electrospun scaffold of poly(glycolide-co-trimethylene carbonate) and gelatin. The scaffold supported in vitro tumorigenesis from CD24(+)CD44(+) cancer stem cells for up to 7 days without inducing apoptosis. Moreover, CD24(+)CD44(+) cancer stem cells delivered by the scaffold grew into a native-like mature pancreatic tumor within 8 weeks in vivo and exhibited accelerated tumorigenesis as well as a higher incidence of tumor formation than the traditional model. In the scaffold model, we discovered that oxaliplatin-gemcitabine (OXA-GEM), a chemotherapeutic regimen, induced tumor regression whereas gemcitabine alone only capped tumor growth. The mechanistic study attributed the superior antitumorigenic performance of OXA-GEM to its ability to induce apoptosis of CD24(+)CD44(+) cancer stem cells. Compared with the traditional model, the scaffold model demonstrated a higher incidence of tumor formation and accelerated tumor growth. Use of a tiny population of highly homogenous CD24(+)CD44(+) cancer stem cells delivered by a well defined scaffold greatly reduces the variability associated with the traditional model, which uses a heterogeneous tumor cell population and poorly defined Matrigel. The scaffold model is a robust platform for investigating the antitumorigenesis mechanism of novel chemotherapeutic drugs with a special focus on cancer stem cells.
authors: Department of Orthopedic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China.
authors: Qingyi
authors: Q
authors: He
authors: Xiaohui
authors: X
authors: Wang
authors: Xing
authors: X
authors: Zhang
authors: Huifang
authors: H
authors: Han
authors: Baosan
authors: B
authors: Han
authors: Jianzhong
authors: J
authors: Xu
authors: Kanglai
authors: K
authors: Tang
authors: Zhiren
authors: Z
authors: Fu
authors: Hao
authors: H
authors: Yin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008819:Mice, Nude; D057139:Nanofibers / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D054457:Tissue Scaffolds / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: cancer stem cell; electrospun scaffold; gemcitabine; oxaliplatin; pancreatic cancer
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