title: A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation.
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.
authors.affiliation: Thoracic Surgery Research Laboratory, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Jarrod D
authors.initials: JD
authors.lastname: Predina
authors.forename: Brendan
authors.initials: B
authors.lastname: Judy
authors.forename: Zvi G
authors.initials: ZG
authors.lastname: Fridlender
authors.forename: Louis A
authors.initials: LA
authors.lastname: Aliperti
authors.forename: Brian
authors.initials: B
authors.lastname: Madajewski
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Jon
authors.initials: J
authors.lastname: Quatromoni
authors.forename: Olugbenga
authors.initials: O
authors.lastname: Okusanya
authors.forename: Sunil
authors.initials: S
authors.lastname: Singhal
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000068579:Celecoxib; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D011183:Postoperative Complications / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013529:Surgical Wound Dehiscence / Q000139:chemically induced; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D000068579:Celecoxib