Surgical Stress Promotes Tumor Growth in Ovarian Carcinoma

Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Clinical Cancer Research (Impact Factor: 8.72). 04/2009; 15(8):2695-702. DOI: 10.1158/1078-0432.CCR-08-2966
Source: PubMed


Surgical stress has been suggested to facilitate the growth of preexisting micrometastases as well as small residual tumor postoperatively. The purpose of this study was to examine the effects of surgical stress on ovarian cancer growth and to determine underlying mechanisms responsible for increased growth.
To mimic the effects of surgery, we did a laparotomy or mastectomy under isoflurane inhalation on athymic nude mice 4 days after i.p. tumor cell injection. Propranolol infusion via Alzet pumps was used to block the influence of sympathetic nervous system activation by surgical stress.
In both HeyA8 and SKOV3ip1 models, the mice in the laparotomy and mastectomy groups had significantly greater tumor weight (P < 0.05) and nodules (P < 0.05) compared with anesthesia only controls. There was no increase in tumor weight following surgery in the beta-adrenergic receptor-negative RMG-II model. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for beta-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment.
These results indicate that surgical stress could enhance tumor growth and angiogenesis, and beta-blockade might be effective in preventing such effects.

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Available from: Guillermo N Armaiz-Pena, Nov 17, 2014
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    • "Surgery is a key cancer therapy and is still the most effective means to treat human solid cancers, which have not yet metastasised (Ceelen et al, 2013). However, tissue damage is implicated as a possible trigger in the development of various cancers (Combemale et al, 2007; Lee et al, 2009; Kasper et al, 2011; Senet et al, 2012) and may provide a favourable niche for tumour reoccurrence (Hofer et al, 1998), as well as facilitating the growth of pre-existing micro-metastases (Bogden et al, 1997), suggesting that surgery may have clinical consequences beyond simply removing the primary cancer (Kuraishy et al, 2011; O&apos;Leary et al, 2013). Classic studies have shown that wounding can lead to tumourigenesis (Hennings & Boutwell, 1970; Clark-Lewis & Murray, 1978; Leder et al, 1990); for example, wounding Rous sarcoma virus-infected chickens led to 100% tumour formation at the injured site (Sieweke et al, 1990), and transgenic mice carrying the v-jun oncogene developed dermal fibrosarcomas after full thickness wounding, whereas identical wounds in non-transgenic mice healed without tumour formation (Schuh et al, 1990). "
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    ABSTRACT: There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal". However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of Ras(G12V)-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    The EMBO Journal 07/2015; 34(17). DOI:10.15252/embj.201490147 · 10.43 Impact Factor
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    • "It was reported that propranolol inhibited the promigratory effect of norepinephrine and reduced metastases formation in BALB/c nude mice (Palm et al., 2006). Wound healing and tumor progression both involve similar processes such as cell proliferation, inflammation, and angiogenesis (Lee et al., 2009). One of the important characters related to process of tumor cell penetration is motility. "
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    ABSTRACT: Abstract Context: Propranolol, atenolol, and ICI118,551 are non-selective β-adrenergic receptor (AR), β1-AR, and β2-AR antagonists, respectively. Objective: We investigated the efficacy of propranolol, atenolol, and ICI118,551 on proliferation, migration, and invasion of non-stimulated breast (MCF7), colon (HT-29), and hepatocellular (HepG2) cancer cells. Materials and methods: β-AR expression profiling of cells was performed by real time PCR. Cell proliferation was determined by MTT. Boyden chamber and scratch assays were performed to evaluate invasion and migration. Results and discussion: All cell lines expressed β-ARs. ICI118,551 was the most cytotoxic, whereas atenolol was the least effective β-AR antagonist for 24, 48, and 72 h. Cell invasion was inhibited by ICI118,551 (45, 46, and 50% for MCF7, HT29, and HepG2, respectively) and propranolol (72, 65, and 90% for MCF7, HT29, and HepG2, respectively). Propranolol, atenolol, and ICI118,551 reduced migration of MCF7, HT-29, and HepG2 cells to varying extents depending on the application concentration and duration. Propranolol and atenolol reduced migration of MCF7 and HT-29 in a concentration-dependent manner, whereas migration of these cells decreased after 48 and 72 h of ICI118,551 applications. Conclusion: Beta2-AR antagonist seemed to be the most cytotoxic β-blocker on non-stimulated cancer cells. Propranolol and ICI118,551 were more effective than atenolol in inhibiting invasion and migration of non-stimulated MCF7 and HT-29 cells; ICI118,551 being the most potent. Concordantly, β2-selective blockage seemed to be more effective for non-stimulated cells. Effect of the selective β-AR antagonists showed variation depending on the concentration, incubation time, and histological origin of cells.
    Pharmaceutical Biology 07/2014; 52(11):1-8. DOI:10.3109/13880209.2014.892513 · 1.24 Impact Factor
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    • "Substantial numbers of patients receiving androgen-ablation therapy with androgen receptor antagonists may need subsequent surgery to treat complications of prostate cancer or for unrelated reasons [3]–[5]. Surgery has been reported to facilitate growth of several types of tumors, including colon and ovarian cancer [6]–[8]. However, effects of surgical stress on apoptosis and prostate involution after androgen ablation therapy have not been studied. "
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    ABSTRACT: Androgens control growth of prostate epithelial cells and androgen deprivation induces apoptosis, leading to prostate involution. We investigated the effects of surgical stress on prostate involution induced by androgen ablation and determined the underlying mechanisms. Androgen ablation in mice was induced by surgical castration and administration of the anti-androgenic drugs bicalutamide and MDV3100. Surgical stress was induced by sham castration under isoflurane anesthesia. Surgical stress delayed apoptosis and prostate involution induced by anti-androgenic drugs. These effects of stress were prevented by administering the selective beta2-adrenoreceptor antagonist ICI118,551 and were also blocked in BAD(3SA/WT) mice expressing phosphorylation-deficient mutant BAD3SA. These results indicate that apoptosis and prostate involution in response to androgen ablation therapy could be delayed by surgical stress via the beta2-adrenoreceptor/BAD signaling pathway. Thus, surgery could interfere with androgen ablation therapy, whereas administration of beta2-adrenoreceptor antagonists may enhance its efficacy.
    PLoS ONE 11/2013; 8(11):e78175. DOI:10.1371/journal.pone.0078175 · 3.23 Impact Factor
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