Surgery promotes implantation of disseminated tumor cells, but does not increase growth of tumor cell clusters

Raa, Sander Ten; Oosterling, Steven J.; Kaaij, Niels P. van der; Tol, M.P. van den; Beelen, Robert H.J.; Meijer, Sybren; Eijck, Casper H.J. van; Sijp, Joost R.M. van der; Egmond, Marjolein van; Jeekel, J.

doi:10.1002/jso.20273

Cited by 53 publications

(31 citation statements)

References 33 publications

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“…Thus, no surgical manipulation was performed. However, studies have demonstrated that surgical manipulation represents the most important factor in peritoneal tumor dissemination [40,41]. In the future, it should be investigated whether surgical manipulation in the setting of different surgical environments, including laparotomy and CO 2 pneumoperitoneum, affect tumor growth and dissemination.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying postoperative peritoneal tumor dissemination may differ between a laparotomy and carbon dioxide pneumoperitoneum: a syngeneic mouse model with controlled respiratory support

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying postoperative peritoneal tumor dissemination may differ between a laparotomy and carbon dioxide pneumoperitoneum: a syngeneic mouse model with controlled respiratory support

et al. 2008

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“…It has been shown that surgery-associated inflammatory reactions are not limited to the resection area but spread out systemically (12,13). Even enhanced tumor recurrence at distant sites has been observed after surgery (14). Elevated levels of the proinflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor a (TNFa) in the peripheral blood after major abdominal surgery have been described (12,13).…”

Section: Introductionmentioning

confidence: 99%

Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and Metastasis

et al. 2008

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Chronic inflammation has been implicated in the pathogenesis of many severe autoimmune disorders, as well as in diabetes, pulmonary diseases, and cancer. Inflammation accompanies most solid cancers including pancreatic ductal adenocarcinoma (PDAC), one of the most fatal cancers with surgery being the only curative therapeutic approach currently available. In the present work, we investigated the role of the major proinflammatory cytokine tumor necrosis factor A (TNFA) in the malignancy of PDAC cells in vitro and in vivo. In vitro, TNFA strongly increased invasiveness of Colo357, BxPc3, and PancTuI cells and showed only moderate antiproliferative effect. TNFA treatment of mice bearing orthotopically growing PDAC tumors led to dramatically enhanced tumor growth and metastasis. Notably, we found that PDAC cells themselves secrete TNFA. Although inhibition of TNFA with infliximab or etanercept only marginally affected proliferation and invasiveness of PDAC cells in vitro, both reagents exerted strong antitumoral effects in vivo. In severe combined immunodeficient mice with orthotopically growing Colo357, BxPc3, or PancTuI tumors, human-specific anti-TNF antibody infliximab reduced tumor growth and metastasis by about 30% and 50%, respectively. Importantly, in a PDAC resection model performed with PancTuI cells, we found an even stronger therapeutic effect for both anti-TNF compounds. Infliximab and etanercept reduced the number of liver metastases by 69% and 42%, respectively, as well as volumes of recurrent tumors by 73% and 51%. Thus, tumor cell-derived TNFA plays a profound role in malignancy of PDAC, and inhibition of TNFA represents a promising therapeutic option particularly in adjuvant therapy after subtotal pancreatectomy.

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“…In a clinical study, Busch et al [1] suggested an association between recurrent tumour disease and extent of surgical injury. It has also become evident from experimental studies [2, 3] that enhanced tumour cell adherence and tumour growth are inevitable repercussions of surgical peritoneal trauma. The pathogenesis of the processes responsible for postoperative intra-abdominal tumour recurrence is only partly clarified.…”

Section: Introductionmentioning

confidence: 99%

The Post-Surgical Inflammatory Response Provokes Enhanced Tumour Recurrence: A Crucial Role for Neutrophils

et al. 2007

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Background/Aims: Peritoneal trauma activates a cascade of peritoneal defence mechanisms responsible for postoperative intra-abdominal tumour recurrence. After peritoneal trauma, inflammatory cells and soluble factors are present in the abdominal cavity and can be captured in lavage fluids. The present study evaluated which component enhances intra-abdominal tumour recurrence. Furthermore, we evaluated which inflammatory cells are present and studied the influence of anti-neutrophil serum (ANS) on peritoneal tumour recurrence. Methods: In a peritoneal trauma model in rats, postoperative lavage fluids were collected and separated into cellular and supernatant components. Both components were injected in naïve rats together with CC531s colon carcinoma cells. In a second experiment, rats were treated with one or three doses of ANS. Results: Intraperitoneal injection of naïve recipients with inflammatory cells or supernatant resulted in significant tumour recurrence. Severe peritoneal trauma provoked significant intra-abdominal neutrophil influx which could be prevented by ANS. Treatment with one dose did not affect blood cell counts and significantly reduced tumour recurrence. Treatment with three doses of ANS decreased blood lymphocytes, monocytes, and neutrophils and induced tumour load. Conclusions: Neutrophils play a crucial role in postoperative adhesion and growth of spilled tumour cells after surgical peritoneal trauma. Prevention of peritoneal neutrophil influx reduces local tumour recurrence.

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Surgery promotes implantation of disseminated tumor cells, but does not increase growth of tumor cell clusters

Abstract: The (post) surgical intra-peritoneal microenvironment enhances successful implantation of spilled tumor cells, whereas growth of adhered tumor cell clusters is not affected. The inflammatory response as a result of remote surgery promotes successful tumor development as well.

Cited by 53 publications

References 33 publications

Molecular mechanisms underlying postoperative peritoneal tumor dissemination may differ between a laparotomy and carbon dioxide pneumoperitoneum: a syngeneic mouse model with controlled respiratory support

Molecular mechanisms underlying postoperative peritoneal tumor dissemination may differ between a laparotomy and carbon dioxide pneumoperitoneum: a syngeneic mouse model with controlled respiratory support

Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and Metastasis

The Post-Surgical Inflammatory Response Provokes Enhanced Tumour Recurrence: A Crucial Role for Neutrophils

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