Accepted Manuscript Title: The effects of surgery-induced immunosuppression and angiogenesis on tumour growth Author: Tsuyoshi Kadosawa PII: DOI: Reference:
S1090-0233(15)00151-3 http://dx.doi.org/doi:10.1016/j.tvjl.2015.04.009 YTVJL 4478
To appear in:
The Veterinary Journal
Accepted date:
7-4-2015
Please cite this article as: Tsuyoshi Kadosawa, The effects of surgery-induced immunosuppression and angiogenesis on tumour growth, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Review The effects of surgery-induced immunosuppression and angiogenesis on tumour growth Tsuyoshi Kadosawa* Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan * Corresponding author. Tel.: +81-11-388-4889 E-mail address: [email protected] (Tsuyoshi Kadosawa)
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Highlights
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Surgical resection is usually the first choice of treatment for localised tumours.
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Surgical stress often triggers the proliferation of dormant micrometastases.
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Surgery induces the activation of angiogenesis with vascularisation of dormant
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tumours.
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Surgery induces dysfunction in immune surveillance of disseminated tumour cells.
Surgeons must take steps against surgery-induced immunosuppression and angiogenesis.
Abstract
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Surgical removal of primary tumours can help in the treatment of cancer but
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carries the risk of triggering the proliferation of dormant micrometastases. Many
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experimental and clinical studies have demonstrated that anti-angiogenic mechanisms
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and immune surveillance are essential to inhibit metastatic tumour cells from growing.
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As surgical stress often induces a reduction in anti-angiogenic factors in parallel with
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increases in angiogenic factors and suppression of immune surveillance during the
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post-operative period, new strategies for peri-operative immunostimulation and
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chemotherapy are required. This review summarizes the factors and proposed
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mechanisms underlying the effects of surgery on immunosuppression and
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angiogenesis.
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Keywords: Angiogenesis; Dormancy. Micrometastases; Immunosuppression;
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Oncology; Surgical stress
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Introduction Surgical resection is usually the first choice of treatment for the management
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of localised malignant tumours, and offers the best chance of a cure. However, many
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patients die of recurrence or metastasis even after complete resection. In human
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medicine, clinical investigations and experimental tumour model studies suggest that
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surgical resection may accelerate the development of metastases by promoting
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increases in the proliferation of residual tumour cells. Several mechanisms for this
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phenomenon have been proposed (Fig. 1), including dissemination of tumour cells
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during surgery (Yamaguchi et al., 2000), blood loss and transfusion (Atzil et al., 2008),
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anaesthetic and analgesic drugs (Melamed et al., 2003), decreased levels of
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anti-angiogenic factors, local and systemic increase in pro-angiogenic and growth
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factors (Hofer, 1999), and suppression of cell-mediated immunity (Shakhar et al.,
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2003). In this article, the mechanisms of immunosuppression and angiogenesis after
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surgical removal of tumours that are more frequently reported are reviewed.
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Growth of distant tumours
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Experimental studies
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A century ago, Ehrlich and Apolant (1905) performed experiments using
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double inoculations of rat sarcomas and observed the retarded growth of the tumour
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subsequently inoculated compared with the primary tumour (Ehrlich and Apolant,
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1905). They also recognised the effects of the primary tumour on tumour growth at
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distant sites. Subsequently, Marie and Clunet (1910) found that implanted tumours that
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rarely produced spontaneous metastases frequently generated metastases when the
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primary implant tumour was incompletely excised (Marie and Clunet, 1910). They
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demonstrated that surgical resection might enhance metastatic development.
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Hadfield (1954) advocated the concept of the dormant cancer cell in 1954; it
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was characterised by prolonged survival in tissues, showing no evidence of
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multiplication during this time while retaining its former and vigorous capacity to
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multiply. The concept was supported by the Fisher brothers’ experiments on the effect
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of partial hepatectomy or sham hepatectomy, and their observations of the
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development of hepatic metastases (Fisher and Fisher, 1959).
70 71
Further findings, such as the relationship between tumours at different sites,
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surgery-related effects and tumour dormancy, have been reported. Gershon et al.
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(1968) suggested that tumour-bearing animals might be refractory to re-inoculation
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with a number of identical tumour cells that were 100,000 times higher than the
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number required to produce primary tumours, while removal of the tumour may
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rapidly result in the appearance of metastatic deposits. Furthermore, Yuhas and
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Pazmino (1974) reported that tumour growth at subcutaneous injection sites was
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depressed in mice that had artificially induced metastases.
79 80
Clinical investigations
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Surgeons practicing human and veterinary medicine have long suspected that
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surgery facilitates the metastatic process, but it is difficult to demonstrate this
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phenomenon.
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adenocarcinoma for 23 years showed no survival benefit of radical prostatectomy
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(Iversen et al., 1995). Similar results were observed in canine prostate cancer (Cornell
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et al., 2000). A prospective cohort study of 1173 patients with breast cancer examining
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the death-specific hazard rate, showed an early first peak 3–4 years after mastectomy
A randomised
study
following
111
humans
with
prostatic
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compared with 4–5 years in untreated patients (Demicheli et al., 2001). This finding
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indicates that the natural history of breast cancer may be adversely altered by tumour
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removal. Moreover, veterinary surgeons often encounter cats that develop pulmonary
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metastases soon after the removal of mammary carcinomas > 3 cm in size (MacEwen
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et al., 1984).
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The degree of surgical stress has been shown to influence outcome. Open
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resection of colorectal cancer was associated with shorter disease-free intervals (DFIs)
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and time-to-recurrence (TTR) compared with laparoscopic resection (Lacy et al., 2002).
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In a study of total cystectomy for canine bladder transitional carcinoma (Kadosawa,
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2012), where surgery was limited to cases without lymph node involvement, distant
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metastasis was assessed by diagnostic imaging, and about half of the cases had ureteral
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dilations in the long-term course of the disease, metastatic progress occurred in
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approximately one-third of cases within 6 months of surgery.
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Proposed mechanisms
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Immunosuppression
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The immune system plays an important role in host protection against
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pathogens such as viruses, bacteria and parasites, and also against tumour cells. Burnet
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(1967) coined the term ‘immune surveillance’ to describe the ability of the immune
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system, especially cell-mediated immunity, to recognise and destroy transformed cells.
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Tumour immunity has been supported by many clinical and experimental
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studies. Pre-existing immune–tumour interactions and lymphocytic responses against
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excised autologous tumour tissue in vitro were reported to predict long-term survival
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rates better than tumour stage and grade (Uchida et al., 1990; McCoy et al., 2000).
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There is an increased frequency of certain malignancies and a dramatic increase in
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metastatic progression in immunocompromised patients, including those receiving
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immunosuppressive drugs (Penn, 1993; Detry et al., 2000) and those that carry
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anti-lymphocyte antibodies (Decaens et al., 2006). The cytotoxic
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T-lymphocyte-associated protein 4 (CTLA-4) receptor blocker, ipilimumab, which
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enhances T-cell-mediated anti-tumour immunity, was shown to increase the survival
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time of patients with metastatic or unresectable melanoma (Postow et al., 2011).
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From a long-term perspective, surgical resection of the primary tumour is
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immunologically beneficial as it will restore anti-tumour immune responses by
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abolishing tumour-dependent immunosuppression (Pollock et al., 1989). However,
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from a short-term perspective, surgical stress often induces dysfunction in immune
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surveillance and outgrowth of disseminated tumour cells into overt metastases.
127 128
Stress hormones, especially catecholamines, opioids and glucocorticoids, have
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been shown in animal models to causally promote metastatic progression through
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immunological and non-immunological mechanisms (Shakhar and Ben-Eliyahu, 1998;
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Shavit et al., 2004; Benish et al., 2008; Goldfarb et al., 2009; Inbar et al., 2011). In
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clinical studies, surgery and the associated neuroendocrine and paracrine responses
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were shown to increase the secretion of immune suppressing hormones, to decrease the
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numbers and activity of natural killer (NK), Th1 and cytotoxic T lymphocyte (CTL)
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cells, and to reduce interleukin-12 (IL-12) and interferon- γ (IFN-γ) expression
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(Greenfeld et al., 2007; Bartal et al., 2010).
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Post-operative changes in lymphocyte counts and transformation responses
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usually returned to normal values within a week, whereas depression of specific
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cellular immunity to tumour-associated antigens in vitro and delayed cutaneous
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hypersensitivity reactions in vivo persisted for about 1 week and gradually returned to
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normal by 3 weeks (Lee, 1977). In dogs undergoing ovariohysterectomy, T
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lymphocyte function, based on blastogenesis to phytohaemagglutinin in vitro, was
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depressed for 24 h after surgery (Medleau et al., 1983). Regulatory T cells (Tregs), a
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subset of T cells with immunosuppressive function, were significantly increased on
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day 6 after surgery (Saito et al., 2013). Similar results were observed in dogs (Watabe
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et al., 2012), where the relative percentage of Tregs increased on day 2 and decreased
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until 2 weeks after surgery.
149 150
Angiogenesis
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Angiogenesis plays an important role in normal tissue expansion, wound
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healing and remodelling, and also in tumour growth and spread. Folkman (1985)
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demonstrated that when a primary tumour was present, metastatic growth was
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suppressed by circulating angiogenesis inhibitors (angiostatin and endostatin). Surgical
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removal of the primary tumour induces the activation of angiogenesis, and temporarily
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causes dormant distant micrometastases to vascularise and thus to enter a rapid growth
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phase.
158 159
The study of biological fluids in patients undergoing surgical procedures has
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also been revealing. Vascular endothelial growth factor (VEGF) increases
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post-operatively in the sera of patients undergoing surgery for lung (Maniwa et al.,
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1998), gastric (Ikeda et al., 2002) and colon (Lacy et al., 2002) cancer. For breast
Page 7 of 18
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cancer, the wound drainage fluid was found to include epidermal growth factor
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(EGF)-like growth factors (Tagliabue et al., 2003), VEGF (Hormbrey 2003; Wu et al.,
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2003) and other unidentified proliferation inducers (Tagliabue et al., 2003) at levels
166
significantly higher than the corresponding serum levels.
167 168
Endothelial-like vascular progenitor cells (VPCs) are circulating in the
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peripheral blood and contributing to new blood vessel formation in the damaged
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tissues and also in the tumours (Rabelink et al., 2004). VPC recruitment following
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tumour resection may depend on tumour subtype and may relate to the degree of
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surgical stress and vascular injury (Javidnia et al., 2014). In contrast, the angiogenesis
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inhibitors endostatin and angiostatin are not detectable in sera shortly after tumour
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excision (O’Reilly et al., 1994; Holmgren et al., 1995; Li et al., 2001; Lacy et al.,
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2002). Thrombospondins (TSP-1 and TSP-2) are also potent endogenous inhibitors of
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angiogenesis (Lawler and Lawler 2012). TSP-1 expression is associated with prognosis
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in many malignant tumours (Miyata et al., 2013; Sun et al., 2014).
178 179
Therapeutic options
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Immunostimulation
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Several immunostimulation approaches have shown promise during the
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peri-operative period. Pre-operative IL-2-induced neutralisation of post-operative
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lymphocytopenia is associated with prolonged survival times in advanced colorectal
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cancer patients (Brivio et al., 1996). Pre-operative administration of replicating viruses,
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such as novel anti-cancer oncolytic viruses, and non-replicating viral vaccines, such as
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influenza vaccination, was reported to prevent post-operative NK-cell dysfunction (Tai
187
et al., 2013). In tumour-bearing mice, a Th1-directed viral infection that triggered
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upregulation of TSP-1 in CD4+ and CD8+ T cells could inhibit tumour angiogenesis
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and suppress tumour growth (Schadler et al., 2014). This report may advocate for
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novel immunotherapy with antiangiogenic surveillance. Prophylactic CpG-C ODN
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(Goldfarb et al., 2009) and ulinastatin (Momosaki et al., 2014) were reported to
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improve immunocompetence and potentially reduce metastatic dissemination in animal
193
models.
194 195
In dogs with malignant tumours, low-dose cyclophosphamide with or without
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toceranib significantly decreased the number and percentage of Tregs in the peripheral
197
blood (Burton et al., 2011; Mitchell et al., 2012).
198 199
Perioperative chemotherapy
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Anti-angiogenesis therapies using endostatin, angiostatin, anti-VEGF, and
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monoclonal antibodies may be protective during the post-operative period (Kerbel,
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2001; Folkman, 2006). Toceranib, a tyrosine kinase inhibitor targeting the VEGF
203
receptor, platelet-derived growth factor (PDGF) receptor and Kit, is thought to have an
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anti-angiogenic effect that contributes to tumour regression in dogs with malignant
205
tumours (London et al., 2012). However, based on the mechanistic similarities of
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physiological and pathological angiogenesis, patients undergoing surgery might be
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subjected to problems with angiogenesis-dependent processes such as wound healing,
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anastomotic healing and liver regeneration, thereby increasing the risk of
209
post-operative complications (von den Bilt and Borel Rinkes, 2004).
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Systemic low-dose continuous treatment of a rat prostate cancer model with
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cyclophosphamide and paclitaxel induced the expression of TSP in tumour tissue and
Page 9 of 18
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inhibited tumour growth (Damber et al., 2006).
214 215
The combination of the β-adrenergic antagonist propranolol and the COX-2
216
inhibitor etodolac significantly improved survival rates in murine tumour models of
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spontaneous post-operative metastasis (Glasner et al., 2010). Surgery markedly
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reduced NK cytotoxicity and NK cell expression of Fas ligand and CD11a, reduced the
219
number of all circulating lymphocyte subtypes, and increased corticosterone levels.
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Propranolol and etodolac administration counteracted these perturbations.
221 222
Blocking the COX-2 pathway has been shown to facilitate tumour cell
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apoptosis (Roche-Nagle et al., 2004; Sinicrope and Gill, 2004), to reduce the levels of
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pro-angiogenic agents (Sinicrope and Gill, 2004; Wei et al., 2004), to increase serum
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endostatin (Ma et al., 2002), to decrease tumour microvascular density (Roche-Nagle
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et al., 2004) and to lower the vascular invasive capacity of tumours by reducing local
227
inflammation and vascular permeability (Condeelis and Pollard, 2006).
228 229
Prediction
230
The immune cell redistribution that is induced by the stress of surgery can
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predict and may partially mediate post-operative healing and recovery (Rosenberger et
232
al., 2009). These findings may provide the basis for identifying patients who are likely
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to show good (as opposed to poor) recovery following surgery and for designing
234
interventions that would maximise protective immune responses and enhance the rate
235
and extent of recovery.
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Conclusions
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Surgical techniques for the removal of tumours will continue to improve and
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undergo refinements, but there is a need for an understanding of the biological changes
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induced by surgery. Surgeons should pay attention to the effects of anaesthesia,
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infection, blood transfusions, and surgical stress-induced immunosuppression and
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angiogenesis on tumour growth, and attempt to circumvent them to maximise any
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potential therapeutic benefits.
244 245
Conflict of interest statement
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None of the authors of this paper has a financial or personal relationship with
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other people or organisations that could inappropriately influence or bias the content of
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this paper.
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Figure legend Fig. 1. A schematic overview of the proposed mechanisms for surgery-inducing tumour growth. The dissemination of tumour cells during surgery, blood loss and transfusion, anaesthetic and analgesic drugs, decreased levels of anti-angiogenic factors (angiostatin and endostatin), local and systemic increase in pro-angiogenic and growth factors (e.g. VEGF), and the suppression of cell-mediated immunity (decrease of cytotoxic T lymphocyte and natural killer cells, increase of regulatory T cells) have been proposed.
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S1090-0233(15)00151-3 http://dx.doi.org/doi:10.1016/j.tvjl.2015.04.009 YTVJL 4478
To appear in:
The Veterinary Journal
Accepted date:
7-4-2015
Please cite this article as: Tsuyoshi Kadosawa, The effects of surgery-induced immunosuppression and angiogenesis on tumour growth, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 2 3 4 5 6 7 8 9 10 11 12
Review The effects of surgery-induced immunosuppression and angiogenesis on tumour growth Tsuyoshi Kadosawa* Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan * Corresponding author. Tel.: +81-11-388-4889 E-mail address: [email protected] (Tsuyoshi Kadosawa)
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Page 1 of 18
14
Highlights
15
Surgical resection is usually the first choice of treatment for localised tumours.
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Surgical stress often triggers the proliferation of dormant micrometastases.
17
Surgery induces the activation of angiogenesis with vascularisation of dormant
18 19
tumours.
20 21 22 23
Surgery induces dysfunction in immune surveillance of disseminated tumour cells.
Surgeons must take steps against surgery-induced immunosuppression and angiogenesis.
Abstract
24
Surgical removal of primary tumours can help in the treatment of cancer but
25
carries the risk of triggering the proliferation of dormant micrometastases. Many
26
experimental and clinical studies have demonstrated that anti-angiogenic mechanisms
27
and immune surveillance are essential to inhibit metastatic tumour cells from growing.
28
As surgical stress often induces a reduction in anti-angiogenic factors in parallel with
29
increases in angiogenic factors and suppression of immune surveillance during the
30
post-operative period, new strategies for peri-operative immunostimulation and
31
chemotherapy are required. This review summarizes the factors and proposed
32
mechanisms underlying the effects of surgery on immunosuppression and
33
angiogenesis.
34 35 36
Keywords: Angiogenesis; Dormancy. Micrometastases; Immunosuppression;
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Oncology; Surgical stress
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38 39
Introduction Surgical resection is usually the first choice of treatment for the management
40
of localised malignant tumours, and offers the best chance of a cure. However, many
41
patients die of recurrence or metastasis even after complete resection. In human
42
medicine, clinical investigations and experimental tumour model studies suggest that
43
surgical resection may accelerate the development of metastases by promoting
44
increases in the proliferation of residual tumour cells. Several mechanisms for this
45
phenomenon have been proposed (Fig. 1), including dissemination of tumour cells
46
during surgery (Yamaguchi et al., 2000), blood loss and transfusion (Atzil et al., 2008),
47
anaesthetic and analgesic drugs (Melamed et al., 2003), decreased levels of
48
anti-angiogenic factors, local and systemic increase in pro-angiogenic and growth
49
factors (Hofer, 1999), and suppression of cell-mediated immunity (Shakhar et al.,
50
2003). In this article, the mechanisms of immunosuppression and angiogenesis after
51
surgical removal of tumours that are more frequently reported are reviewed.
52 53
Growth of distant tumours
54
Experimental studies
55
A century ago, Ehrlich and Apolant (1905) performed experiments using
56
double inoculations of rat sarcomas and observed the retarded growth of the tumour
57
subsequently inoculated compared with the primary tumour (Ehrlich and Apolant,
58
1905). They also recognised the effects of the primary tumour on tumour growth at
59
distant sites. Subsequently, Marie and Clunet (1910) found that implanted tumours that
60
rarely produced spontaneous metastases frequently generated metastases when the
61
primary implant tumour was incompletely excised (Marie and Clunet, 1910). They
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demonstrated that surgical resection might enhance metastatic development.
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63 64
Hadfield (1954) advocated the concept of the dormant cancer cell in 1954; it
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was characterised by prolonged survival in tissues, showing no evidence of
66
multiplication during this time while retaining its former and vigorous capacity to
67
multiply. The concept was supported by the Fisher brothers’ experiments on the effect
68
of partial hepatectomy or sham hepatectomy, and their observations of the
69
development of hepatic metastases (Fisher and Fisher, 1959).
70 71
Further findings, such as the relationship between tumours at different sites,
72
surgery-related effects and tumour dormancy, have been reported. Gershon et al.
73
(1968) suggested that tumour-bearing animals might be refractory to re-inoculation
74
with a number of identical tumour cells that were 100,000 times higher than the
75
number required to produce primary tumours, while removal of the tumour may
76
rapidly result in the appearance of metastatic deposits. Furthermore, Yuhas and
77
Pazmino (1974) reported that tumour growth at subcutaneous injection sites was
78
depressed in mice that had artificially induced metastases.
79 80
Clinical investigations
81
Surgeons practicing human and veterinary medicine have long suspected that
82
surgery facilitates the metastatic process, but it is difficult to demonstrate this
83
phenomenon.
84
adenocarcinoma for 23 years showed no survival benefit of radical prostatectomy
85
(Iversen et al., 1995). Similar results were observed in canine prostate cancer (Cornell
86
et al., 2000). A prospective cohort study of 1173 patients with breast cancer examining
87
the death-specific hazard rate, showed an early first peak 3–4 years after mastectomy
A randomised
study
following
111
humans
with
prostatic
Page 4 of 18
88
compared with 4–5 years in untreated patients (Demicheli et al., 2001). This finding
89
indicates that the natural history of breast cancer may be adversely altered by tumour
90
removal. Moreover, veterinary surgeons often encounter cats that develop pulmonary
91
metastases soon after the removal of mammary carcinomas > 3 cm in size (MacEwen
92
et al., 1984).
93 94
The degree of surgical stress has been shown to influence outcome. Open
95
resection of colorectal cancer was associated with shorter disease-free intervals (DFIs)
96
and time-to-recurrence (TTR) compared with laparoscopic resection (Lacy et al., 2002).
97
In a study of total cystectomy for canine bladder transitional carcinoma (Kadosawa,
98
2012), where surgery was limited to cases without lymph node involvement, distant
99
metastasis was assessed by diagnostic imaging, and about half of the cases had ureteral
100
dilations in the long-term course of the disease, metastatic progress occurred in
101
approximately one-third of cases within 6 months of surgery.
102 103
Proposed mechanisms
104
Immunosuppression
105
The immune system plays an important role in host protection against
106
pathogens such as viruses, bacteria and parasites, and also against tumour cells. Burnet
107
(1967) coined the term ‘immune surveillance’ to describe the ability of the immune
108
system, especially cell-mediated immunity, to recognise and destroy transformed cells.
109 110
Tumour immunity has been supported by many clinical and experimental
111
studies. Pre-existing immune–tumour interactions and lymphocytic responses against
112
excised autologous tumour tissue in vitro were reported to predict long-term survival
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rates better than tumour stage and grade (Uchida et al., 1990; McCoy et al., 2000).
114
There is an increased frequency of certain malignancies and a dramatic increase in
115
metastatic progression in immunocompromised patients, including those receiving
116
immunosuppressive drugs (Penn, 1993; Detry et al., 2000) and those that carry
117
anti-lymphocyte antibodies (Decaens et al., 2006). The cytotoxic
118
T-lymphocyte-associated protein 4 (CTLA-4) receptor blocker, ipilimumab, which
119
enhances T-cell-mediated anti-tumour immunity, was shown to increase the survival
120
time of patients with metastatic or unresectable melanoma (Postow et al., 2011).
121 122
From a long-term perspective, surgical resection of the primary tumour is
123
immunologically beneficial as it will restore anti-tumour immune responses by
124
abolishing tumour-dependent immunosuppression (Pollock et al., 1989). However,
125
from a short-term perspective, surgical stress often induces dysfunction in immune
126
surveillance and outgrowth of disseminated tumour cells into overt metastases.
127 128
Stress hormones, especially catecholamines, opioids and glucocorticoids, have
129
been shown in animal models to causally promote metastatic progression through
130
immunological and non-immunological mechanisms (Shakhar and Ben-Eliyahu, 1998;
131
Shavit et al., 2004; Benish et al., 2008; Goldfarb et al., 2009; Inbar et al., 2011). In
132
clinical studies, surgery and the associated neuroendocrine and paracrine responses
133
were shown to increase the secretion of immune suppressing hormones, to decrease the
134
numbers and activity of natural killer (NK), Th1 and cytotoxic T lymphocyte (CTL)
135
cells, and to reduce interleukin-12 (IL-12) and interferon- γ (IFN-γ) expression
136
(Greenfeld et al., 2007; Bartal et al., 2010).
137
Page 6 of 18
138
Post-operative changes in lymphocyte counts and transformation responses
139
usually returned to normal values within a week, whereas depression of specific
140
cellular immunity to tumour-associated antigens in vitro and delayed cutaneous
141
hypersensitivity reactions in vivo persisted for about 1 week and gradually returned to
142
normal by 3 weeks (Lee, 1977). In dogs undergoing ovariohysterectomy, T
143
lymphocyte function, based on blastogenesis to phytohaemagglutinin in vitro, was
144
depressed for 24 h after surgery (Medleau et al., 1983). Regulatory T cells (Tregs), a
145
subset of T cells with immunosuppressive function, were significantly increased on
146
day 6 after surgery (Saito et al., 2013). Similar results were observed in dogs (Watabe
147
et al., 2012), where the relative percentage of Tregs increased on day 2 and decreased
148
until 2 weeks after surgery.
149 150
Angiogenesis
151
Angiogenesis plays an important role in normal tissue expansion, wound
152
healing and remodelling, and also in tumour growth and spread. Folkman (1985)
153
demonstrated that when a primary tumour was present, metastatic growth was
154
suppressed by circulating angiogenesis inhibitors (angiostatin and endostatin). Surgical
155
removal of the primary tumour induces the activation of angiogenesis, and temporarily
156
causes dormant distant micrometastases to vascularise and thus to enter a rapid growth
157
phase.
158 159
The study of biological fluids in patients undergoing surgical procedures has
160
also been revealing. Vascular endothelial growth factor (VEGF) increases
161
post-operatively in the sera of patients undergoing surgery for lung (Maniwa et al.,
162
1998), gastric (Ikeda et al., 2002) and colon (Lacy et al., 2002) cancer. For breast
Page 7 of 18
163
cancer, the wound drainage fluid was found to include epidermal growth factor
164
(EGF)-like growth factors (Tagliabue et al., 2003), VEGF (Hormbrey 2003; Wu et al.,
165
2003) and other unidentified proliferation inducers (Tagliabue et al., 2003) at levels
166
significantly higher than the corresponding serum levels.
167 168
Endothelial-like vascular progenitor cells (VPCs) are circulating in the
169
peripheral blood and contributing to new blood vessel formation in the damaged
170
tissues and also in the tumours (Rabelink et al., 2004). VPC recruitment following
171
tumour resection may depend on tumour subtype and may relate to the degree of
172
surgical stress and vascular injury (Javidnia et al., 2014). In contrast, the angiogenesis
173
inhibitors endostatin and angiostatin are not detectable in sera shortly after tumour
174
excision (O’Reilly et al., 1994; Holmgren et al., 1995; Li et al., 2001; Lacy et al.,
175
2002). Thrombospondins (TSP-1 and TSP-2) are also potent endogenous inhibitors of
176
angiogenesis (Lawler and Lawler 2012). TSP-1 expression is associated with prognosis
177
in many malignant tumours (Miyata et al., 2013; Sun et al., 2014).
178 179
Therapeutic options
180
Immunostimulation
181
Several immunostimulation approaches have shown promise during the
182
peri-operative period. Pre-operative IL-2-induced neutralisation of post-operative
183
lymphocytopenia is associated with prolonged survival times in advanced colorectal
184
cancer patients (Brivio et al., 1996). Pre-operative administration of replicating viruses,
185
such as novel anti-cancer oncolytic viruses, and non-replicating viral vaccines, such as
186
influenza vaccination, was reported to prevent post-operative NK-cell dysfunction (Tai
187
et al., 2013). In tumour-bearing mice, a Th1-directed viral infection that triggered
Page 8 of 18
188
upregulation of TSP-1 in CD4+ and CD8+ T cells could inhibit tumour angiogenesis
189
and suppress tumour growth (Schadler et al., 2014). This report may advocate for
190
novel immunotherapy with antiangiogenic surveillance. Prophylactic CpG-C ODN
191
(Goldfarb et al., 2009) and ulinastatin (Momosaki et al., 2014) were reported to
192
improve immunocompetence and potentially reduce metastatic dissemination in animal
193
models.
194 195
In dogs with malignant tumours, low-dose cyclophosphamide with or without
196
toceranib significantly decreased the number and percentage of Tregs in the peripheral
197
blood (Burton et al., 2011; Mitchell et al., 2012).
198 199
Perioperative chemotherapy
200
Anti-angiogenesis therapies using endostatin, angiostatin, anti-VEGF, and
201
monoclonal antibodies may be protective during the post-operative period (Kerbel,
202
2001; Folkman, 2006). Toceranib, a tyrosine kinase inhibitor targeting the VEGF
203
receptor, platelet-derived growth factor (PDGF) receptor and Kit, is thought to have an
204
anti-angiogenic effect that contributes to tumour regression in dogs with malignant
205
tumours (London et al., 2012). However, based on the mechanistic similarities of
206
physiological and pathological angiogenesis, patients undergoing surgery might be
207
subjected to problems with angiogenesis-dependent processes such as wound healing,
208
anastomotic healing and liver regeneration, thereby increasing the risk of
209
post-operative complications (von den Bilt and Borel Rinkes, 2004).
210 211
Systemic low-dose continuous treatment of a rat prostate cancer model with
212
cyclophosphamide and paclitaxel induced the expression of TSP in tumour tissue and
Page 9 of 18
213
inhibited tumour growth (Damber et al., 2006).
214 215
The combination of the β-adrenergic antagonist propranolol and the COX-2
216
inhibitor etodolac significantly improved survival rates in murine tumour models of
217
spontaneous post-operative metastasis (Glasner et al., 2010). Surgery markedly
218
reduced NK cytotoxicity and NK cell expression of Fas ligand and CD11a, reduced the
219
number of all circulating lymphocyte subtypes, and increased corticosterone levels.
220
Propranolol and etodolac administration counteracted these perturbations.
221 222
Blocking the COX-2 pathway has been shown to facilitate tumour cell
223
apoptosis (Roche-Nagle et al., 2004; Sinicrope and Gill, 2004), to reduce the levels of
224
pro-angiogenic agents (Sinicrope and Gill, 2004; Wei et al., 2004), to increase serum
225
endostatin (Ma et al., 2002), to decrease tumour microvascular density (Roche-Nagle
226
et al., 2004) and to lower the vascular invasive capacity of tumours by reducing local
227
inflammation and vascular permeability (Condeelis and Pollard, 2006).
228 229
Prediction
230
The immune cell redistribution that is induced by the stress of surgery can
231
predict and may partially mediate post-operative healing and recovery (Rosenberger et
232
al., 2009). These findings may provide the basis for identifying patients who are likely
233
to show good (as opposed to poor) recovery following surgery and for designing
234
interventions that would maximise protective immune responses and enhance the rate
235
and extent of recovery.
236 237
Conclusions
Page 10 of 18
238
Surgical techniques for the removal of tumours will continue to improve and
239
undergo refinements, but there is a need for an understanding of the biological changes
240
induced by surgery. Surgeons should pay attention to the effects of anaesthesia,
241
infection, blood transfusions, and surgical stress-induced immunosuppression and
242
angiogenesis on tumour growth, and attempt to circumvent them to maximise any
243
potential therapeutic benefits.
244 245
Conflict of interest statement
246
None of the authors of this paper has a financial or personal relationship with
247
other people or organisations that could inappropriately influence or bias the content of
248
this paper.
249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275
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Figure legend Fig. 1. A schematic overview of the proposed mechanisms for surgery-inducing tumour growth. The dissemination of tumour cells during surgery, blood loss and transfusion, anaesthetic and analgesic drugs, decreased levels of anti-angiogenic factors (angiostatin and endostatin), local and systemic increase in pro-angiogenic and growth factors (e.g. VEGF), and the suppression of cell-mediated immunity (decrease of cytotoxic T lymphocyte and natural killer cells, increase of regulatory T cells) have been proposed.
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