**6. Surgery, inflammation and tumourigenesis**

At present, the only recognised curative treatment for cancer is surgery. As a result, surgery is the mainstay treatment for tumours. However, surgery is not indicated for all patients with a cancer diagnosis. Surgery is only indicated in these patients if the cancer has not dissipated and spread to distant organs. In fact, surgery in these patients worsens outcome and survival. This begs the question, is surgery tumorigenic? Numerous studies have examined the role of surgery itself on tumour growth. Interestingly, cancer surgery in the presence of micrometastases increases metastatic burden and enhances peri-operative tumour growth (Pigeon, 1999; MS, 1997; Coffey, 2002). The presence of undetected micrometastases is thought to be largely responsible for these recurrences. Cancer patients often harbour micrometastases which are undetectable at the time of surgery. Surgical

lymphocytes (CTL) and antibodies specific for TAA have been demonstrated in patients with cancers including colorectal cancer (Nagorsen, 2000). Therefore there is an ideal niche in cancer treatment for an active specific immunotherapy. Previously identified or undefined TAAs can be administered to cancer patients in order to cause a systemic

Despite the huge amount of evidence and theoretical potential of this treatment strategy, the clinical results are limited to date. There is evidence to support the tumouricidal effects of active specific immunotherapy however it appears cancer cells are able to survive the tumouricidal effects as the disease progresses. This phenomenon has become known as 'tumour immune escape'. Several mechanisms have been proposed as to how this phenomenon occurs. One body of evidence shows evidence that cancer genetic instability leads to TAA/HLA downregulation as well as to disruption of the TAA processing/presenting machinery which then allows malignant cells to evade the surveillance of immune sentinels (Seliger, 2001; Yang, 2003). Another proposed mechanism lies in the ability of cancer cells to produce immunosuppressive cytokines e.g. IL-10, and thus counteract the immune system response (Mocellin, 2001; Walker, 1997). The challenge for tumour immunologists currently is to overcome this 'tumour immune escape' and increase the proportion of patients mounting an immune response and increase the rate of

The role of macrophages in the development of colorectal cancer is controversial. One study demonstrated that increased numbers of macrophages in all areas of the tumour correlated with an advanced tumour stage (Bailey, 2007). On the other hand Forssell et al showed that the presence of macrophages positively influenced prognosis in colorectal cancer (Forssell, 2007). Another group demonstrated that macrophages have the ability to inhibit or stimulate tumour growth according to their polarisation and state of activation (Mantovani, 2005). This group showed that M1-polarised macrophages activated by IFNγ and bacterial products like LPS display tumouricidal effects whereas M2 macrophages differentiated in the presence of Th2 cytokines, IL-4, IL-13 or IL-10, have the opposite effect. These macrophages favour tumour cell proliferation and stimulate tumour progression and tumour invasion. These studies are crucial in demonstrating the important role that inflammatory mediators such as chemokines and cytokines play in the establishment of the tumour microenvironment. The tumorgenicity of proinflammatory mediators such as interleukin-6 and tumour necrosis factor-α (TNFα) was shown by Coussens et al (Coussens,

At present, the only recognised curative treatment for cancer is surgery. As a result, surgery is the mainstay treatment for tumours. However, surgery is not indicated for all patients with a cancer diagnosis. Surgery is only indicated in these patients if the cancer has not dissipated and spread to distant organs. In fact, surgery in these patients worsens outcome and survival. This begs the question, is surgery tumorigenic? Numerous studies have examined the role of surgery itself on tumour growth. Interestingly, cancer surgery in the presence of micrometastases increases metastatic burden and enhances peri-operative tumour growth (Pigeon, 1999; MS, 1997; Coffey, 2002). The presence of undetected micrometastases is thought to be largely responsible for these recurrences. Cancer patients often harbour micrometastases which are undetectable at the time of surgery. Surgical

immune response which will lead to malignant cell destruction (Rosenberg, 2001).

responses from the targeted tumour.

**6. Surgery, inflammation and tumourigenesis** 

2002).

intervention in these patients is thought not only to accelerate their progression but also to be responsible for activating dormant micrometastases that may have remained inactive in the absence of surgery. In addition, the extent of the surgery is proportional to the postoperative recurrence rate. This is evidenced by the meta-analyses that show that minimally invasive surgery is more effective than open surgery in improving tumour recurrence, and cancer-related survival (Hensler, 1997), although equally studies exist that do not support this idea (Jayne, 2010). Considering surgery is the only curative treatment of solid tumours, this knowledge has prompted efforts to understand this undesired effect of surgery. It is hoped that this understanding will eventually help develop therapeutic treatments that may attenuate or eliminate this unwelcome consequence of surgery.

#### **6.1 Mechanisms of surgery induced tumourigenesis**

Considering what is already known concerning the role of inflammation in tumourigenesis, it is not surprising that surgery is tumorigenic. Surgery confers a traumatic insult to the body which like all traumas induce a potent pro-inflammatory response. Surgery is followed by a biologic period of repair to help restore homeostasis. It induces an early hyper-inflammatory response, which is characterised by pro-inflammatory TNF-α, IL-1 and IL-6 cytokine release (Walker, 1999) and neutrophil activation (Hensler, 1997). Several of these cytokines have been shown to potentiate tumour growth (Coussens, 2004). The massive and continuous IL-6 release subsequently accounts for the up-regulation of major anti-inflammatory mediators, such as PGE2, IL-10, and TGF-ß (Walker 1999). The magnitude and duration of this hyper-inflammatory response is proportional to the severity of the trauma which may explain how laparoscopic versus open surgery may result in lower tumour recurrence (Colacchio, 1994; Baigrie, 1992). Following surgery, angiogenesis is also stimulated as the body initiates a period of healing and biological repair. Pro-angiogenic substances such as VEGF become elevated post-operatively. Moreover, anti-angiogenic substances such as endostatin and angiostatin are not detectable in the serum shortly after tumour excision (Li, 2001; Holmgren 1995; O'Reilly, 1994). This incites the formation of capillaries and new blood vessels not only to the areas of tissue insult but also to all parts of the body including areas of residual metastatic disease which promotes tumour growth.

Furthermore, surgery also influences immune system function. Immuno-suppression is a feature of the post-operative stress response and is also associated with anaesthesia, blood transfusion and the release of acute-phase proteins (Lee, 1977). The immune system appears to be an important regulator in identifying and eliminating any abnormal cells with cancerous potential. Hence, any disruption of immune function as a result of surgery can also lead to potentiating tumour growth. Interestingly, this immuno-suppression is greater dependent on the extent of surgery (Da Costa, 1998; Da Costa, 1999). The immunosuppressive effects of surgery can last anywhere from between 4 to 14 days depending on the size of surgical trauma induced but peaks day three post-operatively in most cases. Likewise, this may explain why laparoscopic versus open surgery in colon cancer patients confers a greater survival advantage, although the evidence supporting this is not equivocal.

Endotoxaemia also occurs following surgery involving bowel manipulation. Endotoxin, a potent inflammatory mediator, is a component on the wall of Gram negative bacteria often found in the lumen of the gastrointestinal system. Upon manipulation, endotoxin or LPS translocates across the intestinal lumen and enters the circulation. Endotoxaemia further

The Role of Inflammation in Cancer 403

Arlt A, Vorndamm J, Breitenbroich M, Folsch UR, Kalthoff H, Schmidt WE, Schafer H.

induced by etoposide (VP16) or doxorubicin, Oncogene 20 (2001) 859–868. Asselin E, Mills GB, Tsang BK. XIAP regulates Akt activity and caspase-3-dependent

Baigrie R, Lamont P, Kwiatkowski D, Dallman M, Morris P. Systemic cytokine response

Bailey C, Negus R, Morris A, Ziprin P, Goldin R et al. Chemokine expression is associated

Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? The Lancet

Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls, Nat.

Belvin MP, Anderson KV. A CONSERVED SIGNALING PATHWAY: The Drosophila Toll-

Bharti AC AB. Chemopreventive agents induce suppression of nuclear factor-kappaB leading to chemosensitization. Ann N Y Acad Sci 2002;973(Nov): 392-395. Böhm B, Schwenk W, Hucke H, Stock W. Does methodic long-term follow-up affect survival

Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT et al. 2004. The ubiquitin-modifying

Braumann C, Winkler G, Rogalla P, Menenakos C, Jacobi C. Prevention of disease

Bruserud O, Ryningen A, Wergeland L, Glenjen NI, Gjertsen BT. 2004. Osteoblasts increase

Catz SD, Johnson JL, Transcriptional regulation of bcl-2 by nuclear factor kappa B and its

Coffey J, Doyle M, O'Mahony L. Probiotics confer protection against perioperative

case. World Journal of Surgical Oncology 2006;4(1): 34.

metastatic tumour growth. Ann Surg Oncol 2002;9: 93.

Burnet F. Cancer-A biological approach. 37. Med J 1957;1: 779-841.

myelogenous leukemia blasts. Haematologica 89, 391–402.

significance in prostate cancer, Oncogene 20 (2001) 7342–7351. Cheadle EJ, Jackson AM. (2002) Bugs as drugs for cancer. Immunology 107:10–19

Dorsal Pathway. Annual Review Cell Dev. Biol. 1996. 12:393–416

in human colorectal cancer, Clin. Exp. Metastasis 24 (2007), pp. 121–130 Baldwin, A.S., Jr. (2001). Series introduction: The transcription factor NF-B and human

Balkwill F. Cancer and the Chemokine Network. Nature Reviews, Cancer 2004;4:540–50. Bates RC, DeLeo MJ, Arthur M. The epithelial–mesenchymal transition of colon carcinoma

after major surgery. British Journal of Surgery 1992;79(8): 757–760.

cells. Cancer Res 2001;61:1862–8.

disease. J. Clin. Invest. 107, 3–6.

Rev. Drug Discov. 8 (2009) 33–40 Bell JK. Proc. Natl. Acad. Sci. U.S.A. 102, 10976 (2005).

Experimental Cell Research 299 (2004) 315– 324.

2001;357(9255): 539-545.

1993;36(3): 280-286.

Immunol.5:1052–1060.

Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis

cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer

with the accumulation of tumour associated macrophages (TAMs) and progression

involves expression of IL-8 and CXCR-1-mediated chemotaxis. Mercurio

after curative resection of colorectal carcinoma? Diseases of the Colon & Rectum

enzyme A20 is required for termination of Toll-like receptor responses. Nat.

progression in a patient with a gastric cancer-re-recurrence. Outcome after intravenous treatment with the novel antineoplastic agent taurolidine. Report of a

proliferation and release of pro-angiogenic interleukin 8 by native human acute

potentiates the hyper-inflammatory response following surgery such as colorectal cancer resection. One study examined the effect of endotoxin administration on a murine breast cancer model (Pigeon, 1999). Interestingly, they found enhanced metastatic growth in the endotoxin treated group compared to controls. In a later study the same group found that endotoxin-induced metastatic growth was associated with increased angiogenesis, vascular permeability and tumour cell invasion and migration (Harmey, 2002). Therefore, this is another potential mechanism of surgically induced tumour growth especially in regard to colorectal cancer operations. In addition, the actual manipulation of the tumour during surgery results in the dissemination of tumour cells into the circulation. These tumour cells can potentially seed in distant sites throughout the body facilitating metastatic spread. Surgeons will make efforts to minimise tumour manipulation intra-operatively to minimise this potential.

Peri-operative tumour growth appears to significantly impact on tumour recurrence following "curative" surgery. Following a deeper understanding of this mechanism, therapeutic efforts are now being sought. Peri-operative immunomodulators such as IL-2, known to abrogate the immune changes that follow excisional cancer surgery, are being investigated as potential peri-operative treatments showing promising initial results (Den Otter, 1996). Even current chemotherapeutic regimes known to induce cell death in rapidly dividing cells have been given immediately post-operatively resulting in increased longterm survival. However, most of these treatments are limited by their toxicities as tissue and wound healing are essential in the immediate post-operative period.
