A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation

Jarrod D. Predina, Brendan Judy, Zvi G. Fridlender, Louis A. Aliperti, Brian Madajewski, Veena Kapoor, Guanjun Cheng, Jon Quatromoni, Olugbenga Okusanya, Sunil Singhal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Up to 30% of cancer patients undergoing curative surgery develop local recurrences due to positive margins. Patients typically receive adjuvant chemotherapy, immunotherapy and/or radiation to prevent such relapses. Interestingly, evidence supporting these therapies is traditionally derived in animal models of primary tumors, thus failing to consider surgically induced tumor microenvironment changes that may influence adjuvant therapy efficacy. To address this consideration, we characterized a murine model of local cancer recurrence. This model was reproducible and generated a postoperative inflammatory tumor microenvironment that resembles those observed following human cancer surgery. To further validate this model, antagonists of two pro-inflammatory mediators, TGFβ and COX-2, were tested and found to be effective in decreasing the growth of recurrent tumors. We appreciated that preoperative TGFβ inhibition led to wound dehiscence, while postoperative initiation of COX-2 inhibition resulted in a loss of efficacy. In summary, although not an exact replica of all human cancer surgeries, our proposed local recurrence approach provides a biologically relevant and reliable model useful for preclinical evaluation of novel adjuvant therapies. The use of this model yields results that may be overlooked using traditional preclinical cancer models that fail to incorporate a surgical component.

Original languageEnglish
Pages (from-to)745-755
Number of pages11
JournalCancer Biology and Therapy
Volume13
Issue number9
DOIs
StatePublished - Jul 2012
Externally publishedYes

Keywords

  • Adjuvant therapy
  • Cancer recurrence
  • Immunotherapy
  • Oncology
  • Surgical model
  • Tumor microenvironment

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