Current human colorectal cancer (CRC) orthotopic xenograft models require surgery and do not readily progress to form tumors in liver, the most common site for metastasis. We developed cell and patient-derived xenograft models that use chemokine-targeting to recapitulate the vast majority of recurrent human somatic CRC mutations as primary gastrointestinal (GI) tumors in mice without requiring surgery. Importantly, we incorporate early-stage mouse blastocyst microinjection techniques to extend this approach and demonstrate that it can also model primary human CRCs in immunoproficient mouse hosts. Next, we show that primary GI tumors can inducibly metastasize to liver. Finally, we use this system to demonstrate that human CRC liver metastases in vivo are more chemoresistant than paired sub-cutaneous xenografts. Overall, we anticipate that this resource can help improve our mechanistic understanding of human primary CRC growth, progression to liver metastasis and potentially provide a more physiological model than sub-cutaneous xenograft for pre-clinical drug discovery.
Citation Format: Huanhuan Joyce Chen, Jian Sun, Harry Hou, Winfried Edelmann, Xiling Shen, Steven M. Lipkin. Chemokine-targeted colorectal cancer: improved models of human primary tumor formation, liver metastasis and chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3118. doi:10.1158/1538-7445.AM2014-3118