A Mouse Tumor Model of Surgical Stress to Explore the Mechanisms of Postoperative Immunosuppression and Evaluate Novel Perioperative Immunotherapies

Abstract

Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to the development of metastatic disease in animal models and in cancer patients. Preclinical work from our group and others has demonstrated a profound suppression of innate immune function, specifically NK cells in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Relatively few animal studies and clinical trials have focused on characterizing and reversing the detrimental effects of cancer surgery. Using a rigorous animal model of spontaneously metastasizing tumors and surgical stress, the enhancement of cancer surgery on the development of lung metastases was demonstrated. In this model, 4T1 breast cancer cells are implanted in the mouse mammary fat pad. At day 14 post tumor implantation, a complete resection of the primary mammary tumor is performed in all animals. A subset of animals receives additional surgical stress in the form of an abdominal nephrectomy. At day 28, lung tumor nodules are quantified. When immunotherapy was given immediately preoperatively, a profound activation of immune cells which prevented the development of metastases following surgery was detected. While the 4T1 breast tumor surgery model allows for the simulation of the effects of abdominal surgical stress on tumor metastases, its applicability to other tumor types needs to be tested. The current challenge is to identify safe and promising immunotherapies in preclinical mouse models and to translate them into viable perioperative therapies to be given to cancer surgery patients to prevent the recurrence of metastatic disease.

c-Myb Enhances Breast Cancer Invasion and Metastasis through the Wnt/β-Catenin/Axin2 Pathway

“…Five weeks after injection, all mice were sacrificed and metastases were analyzed. The mouse mammary fat pad implantation was based on previously published methods (18). Female BALB/c mice were anesthetized and used for this assay.…”

Surgical Trauma Leads to a Shorter Survival in a Murine Orthotopic Pancreatic Cancer Model

“…However, HLA-DR is expressed only by humans and therefore not a useful marker in mouse models. Nevertheless, surgery- and trauma-induced severe immunosuppression is also seen in equivalent murine models [8,9,10,11]. …”

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

“…B78H1GM cells were obtained from Dr Elizabeth Jaffee (Johns Hopkins, Baltimore). Cells used during this study were less than passage 30 and confirmed to be free of mycoplasma contamination by Hoescht staining (Thermofisher Cat#62249) as per manufacturer's protocol.…”

“…Routine perioperative care (including anesthesia and pain management) was performed as previously described 8 . Briefly, mice were subjected to 2.5% isofluorane (Baxter Corp.) for induction and maintenance of anesthesia.…”