Surgical Stress Promotes the Development of Cancer Metastases by a Coagulation-Dependent Mechanism Involving Natural Killer Cells in a Murine Model

Seth, Rashmi; Tai, Lee-Hwa; Falls, Theresa; Souza, Christiano Tanese de; Bell, John C.; Carrier, Marc; Atkins, Harold L.; Boushey, Robin P.; Auer, Rebecca C.

doi:10.1097/sla.0b013e31826fcbdb

Cited by 98 publications

(85 citation statements)

References 46 publications

(53 reference statements)

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“…1A, NK cell-intact). In addition, our findings indicate that this prometastatic effect seen following surgery is not mouse strain, cell-type, anesthesia/analgesia, or surgery specific (34).…”

Section: Surgical Stress Increases Lung Metastases and Nk Cells Are Imentioning

confidence: 77%

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

et al. 2013

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Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients. Cancer Res; 73(1); 97-107. Ó2012 AACR.

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Section: Surgical Stress Increases Lung Metastases and Nk Cells Are Imentioning

confidence: 77%

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

et al. 2013

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“…One of the key mechanisms responsible for the prometastatic effects of surgery is postoperative dysfunction of Natural Killer (NK) cells [1][2][3] . NK cells are cytotoxic lymphocytes of the innate immune system involved in the control of tumor growth and metastases 6 .…”

Section: Introductionmentioning

confidence: 99%

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

Tai

Souza

Sahi

et al. 2014

JoVE

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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.

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“…Major thoracic or abdominal surgery is the mainstay of treatment for these top 5 solid cancers to extend the patient’s life. Unfortunately, disease recurs within 5 years in the majority of these patients and they tend to not respond to frontline therapies [1]. Minimal residual disease are occult tumors that persist in the patient following curative surgery.…”

Section: Introductionmentioning

confidence: 99%

Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity

Bakos¹,

Lawson²,

Rouleau³

et al. 2018

j. immunotherapy cancer

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127

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BackgroundCancer surgery is necessary and life-saving. However, the majority of patients develop postoperative recurrence and metastasis, which are the main causes of cancer-related deaths. The postoperative stress response encompasses a broad set of physiological changes that have evolved to safeguard the host following major tissue trauma. These stress responses, however, intersect with cellular mediators and signaling pathways that contribute to cancer proliferation.MainPrevious descriptive and emerging mechanistic studies suggest that the surgery-induced prometastatic effect is linked to impairment of both innate and adaptive immunity. Existing studies that combine surgery and immunotherapies have revealed that this combination strategy is not straightforward and patients have experienced both therapeutic benefit and drawbacks. This review will specifically assess the immunological pathways that are disrupted by oncologic surgical stress and provide suggestions for rationally combining cancer surgery with immunotherapies to improve immune and treatment outcomes.Short conclusionGiven the prevalence of surgery as frontline therapy for solid cancers, the emerging data on postoperative immunosuppression and the rapid development of immunotherapy for oncologic treatment, we believe that future targeted studies of perioperative immunotherapy are warranted.

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Surgical Stress Promotes the Development of Cancer Metastases by a Coagulation-Dependent Mechanism Involving Natural Killer Cells in a Murine Model

Cited by 98 publications

References 46 publications

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

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

Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity

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