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

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 Yin<sup>1,4

1</sup>Department 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 work


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.

Keywords: pancreatic cancer, cancer stem cell, electrospun scaffold, gemcitabine, oxaliplatin