A tissue-engineered subcutaneous pancreatic cancer model for antitumor drug evaluation

Abstract

Qingyi He,2,* Xiaohui Wang,3,* Xing Zhang,4 Huifang Han,4 Baosan Han,5 Jianzhong Xu,2 Kanglai Tang,2 Zhiren Fu,1 Hao Yin1,4 1Department of Surgery, Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai Second Military Medical School, 2Department of Orthopedic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 3Department of General Surgery, Bayinguoleng Mengguzizhizhou People's Hospital, Korla, Xinjiang, People's Republic of China; 4Department of Surgery, The University of Chicago, Chicago, IL, USA; 5Department of Surgery, Shanghai Xinhua Hospital, Shanghai, People's Republic of China*These authors contributed equally to this workAbstract: 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.Keywords: pancreatic cancer, cancer stem cell, electrospun scaffold, gemcitabine, oxaliplatin