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Am J Transl Res 2012;4(2):206-218
Original Article
Characterization of surgical models of postoperative tumor recurrence
for preclinical adjuvant therapy assessment
Jarrod D Predina, Brendan Judy, Veena Kapoor, Aaron Blouin, Louis A Aliperti, Daniel Levine, Olugbenga T
Okusanya, Jon Quatromoni, Zvi G Fridlender, Sunil Singhal
Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, 6 White
Building, 3400 Spruce Street, Philadelphia, PA, 19104; 2Institute of Pulmonary Medicine, Hadassah-Hebrew
University Medical Center, POB 12000, Jerusalem 91120, Israel; 3Division of Pulmonary, Allergy and Critical Care
Medicine, Department of Medicine, University of Pennsylvania School of Medicine, 1015F ARC, 3615 Civic Center
Blvd., Philadelphia, PA 19104, USA
Received January 12, 2012; accepted February 27, 2012; Epub April 10, 2012; Published April 30, 2012
Abstract: Purpose: Nearly 30% of cancer patients undergoing curative surgery succumb to distant recurrent
disease. Despite large implications and known differences between primary and recurrent tumors, preclinical
adjuvant therapy evaluation frequently occurs only in primary tumors and not recurrent tumors. We hypothesized
that well characterized and reproducible models of postoperative systemic recurrences should be used for
preclinical evaluation of adjuvant approaches. Experimental Design: We examined traditional animal models of
cancer surgery that generate systemic cancer recurrences. We also investigated models of systemic cancer
recurrences that incorporate spontaneously metastatic cell lines and surgical resection. For each model, we
critiqued feasibility, reproducibility and similarity to human recurrence biology. Using our novel model, we then
tested the adjuvant use of a novel systemic inhibitor of TGF-β, 1D11. Results: Traditional surgical models are
confounded by immunologic factors including concomitant immunity and perioperative immunosuppression. A
superior preclinical model of postoperative systemic recurrences incorporates spontaneously metastatic cell
lines and primary tumor excision. This approach is biologically relevant and readily feasible. Using this model, we
discovered that “perioperative” TGF-β blockade has strong anti-tumor effects in the setting of advanced disease
that would not be appreciated in primary tumor cell lines or other surgical models. Conclusions: There are
multiple immunologic effects that rendered previous models of postoperative cancer recurrences inadequate.
Use of spontaneously metastatic cell lines followed by surgical resection eliminates these confounders, and best
resembles the clinical scenario. This preclinical model provides more reliable preclinical information when
evaluating new adjuvant therapies. (AJTR1201002).
Keywords: Surgery, recurrence, models, surgical oncology, concomitant immunity, perioperative
immunosuppression, TGF-β
Address all correspondence to:
Dr. Sunil Singhal
Division of Thoracic Surgery
Department of Surgery
University of Pennsylvania School of Medicine
6 White Building, 3400 Spruce Street
Philadelphia, PA, 19104, USA.
E-mail: sunil.singhal@uphs.upenn.edu
Original Article
Characterization of surgical models of postoperative tumor recurrence
for preclinical adjuvant therapy assessment
Jarrod D Predina, Brendan Judy, Veena Kapoor, Aaron Blouin, Louis A Aliperti, Daniel Levine, Olugbenga T
Okusanya, Jon Quatromoni, Zvi G Fridlender, Sunil Singhal
Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, 6 White
Building, 3400 Spruce Street, Philadelphia, PA, 19104; 2Institute of Pulmonary Medicine, Hadassah-Hebrew
University Medical Center, POB 12000, Jerusalem 91120, Israel; 3Division of Pulmonary, Allergy and Critical Care
Medicine, Department of Medicine, University of Pennsylvania School of Medicine, 1015F ARC, 3615 Civic Center
Blvd., Philadelphia, PA 19104, USA
Received January 12, 2012; accepted February 27, 2012; Epub April 10, 2012; Published April 30, 2012
Abstract: Purpose: Nearly 30% of cancer patients undergoing curative surgery succumb to distant recurrent
disease. Despite large implications and known differences between primary and recurrent tumors, preclinical
adjuvant therapy evaluation frequently occurs only in primary tumors and not recurrent tumors. We hypothesized
that well characterized and reproducible models of postoperative systemic recurrences should be used for
preclinical evaluation of adjuvant approaches. Experimental Design: We examined traditional animal models of
cancer surgery that generate systemic cancer recurrences. We also investigated models of systemic cancer
recurrences that incorporate spontaneously metastatic cell lines and surgical resection. For each model, we
critiqued feasibility, reproducibility and similarity to human recurrence biology. Using our novel model, we then
tested the adjuvant use of a novel systemic inhibitor of TGF-β, 1D11. Results: Traditional surgical models are
confounded by immunologic factors including concomitant immunity and perioperative immunosuppression. A
superior preclinical model of postoperative systemic recurrences incorporates spontaneously metastatic cell
lines and primary tumor excision. This approach is biologically relevant and readily feasible. Using this model, we
discovered that “perioperative” TGF-β blockade has strong anti-tumor effects in the setting of advanced disease
that would not be appreciated in primary tumor cell lines or other surgical models. Conclusions: There are
multiple immunologic effects that rendered previous models of postoperative cancer recurrences inadequate.
Use of spontaneously metastatic cell lines followed by surgical resection eliminates these confounders, and best
resembles the clinical scenario. This preclinical model provides more reliable preclinical information when
evaluating new adjuvant therapies. (AJTR1201002).
Keywords: Surgery, recurrence, models, surgical oncology, concomitant immunity, perioperative
immunosuppression, TGF-β
Address all correspondence to:
Dr. Sunil Singhal
Division of Thoracic Surgery
Department of Surgery
University of Pennsylvania School of Medicine
6 White Building, 3400 Spruce Street
Philadelphia, PA, 19104, USA.
E-mail: sunil.singhal@uphs.upenn.edu
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