Surgery-induced reactive oxygen species enhance colon carcinoma cell binding by disrupting the liver endothelial cell lining (original) (raw)
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OncoImmunology
Spillage of bacterial products during colon surgery increases the risk of liver metastases development in a rat colon carcinoma model., OncoImmunology, 7:9, e1461302, ABSTRACT Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal carcinoma (CRC). However, bacterial translocation during intestinal surgery has been correlated with poor long-term oncological outcome. Therefore, we investigated the influence of bacterial contamination during colon surgery on CRC liver metastases development. Blood and liver samples of patients undergoing resection of primary CRC or liver metastases were collected. Cell numbers, activation markers and inflammatory mediators were determined. Tumor cell adhesion and outgrowth after sham-or colectomy operations were determined in a rat model, in which tumor cells had been injected into the portal vein. White blood cells and granulocytes were increased in per-and post-operative patient blood samples. IL-6 was also increased post-operatively compared to the preoperative level. Expression of NOX-2, NOX-4 and polymorphonuclear cells (PMNs) numbers were elevated in post-operative human liver samples. In vitro stimulation of macrophages with plasma of rats after colectomy resulted in production of reactive oxygen species (ROS). Colectomy in rats increased D-lactate levels in plasma, supporting bacterial translocation. Decreased expression of tight junction molecules and increased tumor cell adhesion and outgrowth was observed. Treatment with a selective decontamination of the digestive tract (SDD) cocktail decreased tumor cell adherence after colectomy. In conclusion, postoperative bacterial translocation may activate liver macrophages and PMNs, resulting in ROS production. As we previously showed that ROS release led to liver vasculature damage, circulating tumor cells may adhere to exposed extracellular matrix and grow out into liver metastases. This knowledge is pivotal for development of therapeutic strategies to prevent surgery-induced liver metastases development.
Clinical & experimental metastasis, 2018
Surgery remains the curative treatment modality for colorectal cancer in all stages, including stage IV with resectable liver metastasis. There is emerging evidence that the stress response caused by surgery as well as other perioperative therapies such as anesthesia and analgesia may promote growth of pre-existing micro-metastasis or potentially initiate tumor dissemination. Therapeutically targeting the perioperative period may therefore reduce the effect that surgical treatments have in promoting metastases, for example by combining β-adrenergic receptor antagonists and cyclooxygenase-2 (COX-2) inhibitors in the perioperative setting. In this paper, we highlight some of the mechanisms that may underlie surgery-related metastatic development in colorectal cancer. These include direct tumor spillage at the time of surgery, suppression of the anti-tumor immune response, direct stimulatory effects on tumor cells, and activation of the coagulation system. We summarize in more detail r...
Hepatology, 2007
Currently, an operation is the only curative option for patients with colorectal cancer. Unfortunately, many patients will develop liver metastases even after successful resection of the primary tumor. Removal of primary colorectal carcinoma may paradoxically increase the risk of metastases development, because accumulating evidence suggests that surgical trauma can stimulate tumor growth. In the present study, we investigated the effects of abdominal trauma on liver metastases development. Surgical trauma dramatically increased adhesion of tumor cells in the liver, leading to enhanced outgrowth of metastases. Endothelial stress was observed rapidly after an operation, suggesting that abdominal trauma resulted in impair-
British Journal of Surgery, 2011
Background: Several studies have suggested that laparoscopy might confer an oncological advantage in patients undergoing surgery for colonic cancer. A decreased inflammatory and angiogenic response has been proposed. This study compared the local and systemic inflammatory and angiogenic responses after open and laparoscopic surgery for colonic cancer. Methods: Some 122 patients with colonic cancer were randomized to open or laparoscopic colectomy. Levels of interleukin (IL) 6 and vascular endothelial growth factor (VEGF) were measured in serum and peritoneal fluid at baseline, then at 4, 12, 24 and 48 h and on day 4 after surgery. Samples obtained on day 4 were tested in an in vitro angiogenesis assay, with measurement of number of capillaries per field and capillary length. Results: The serum IL-6 level was lower in the laparoscopic group at 4 h (mean(s.d.) 124(110) versus 244(326) pg/dl after open colectomy; P = 0•027). The serum VEGF concentration was also lower in the laparoscopic group at 48 h and day 4 (430(435) versus 650(686) pg/dl; P = 0•001). Overall, local IL-6 and VEGF levels were significantly higher than serum levels but there were no differences between groups. In vitro, postoperative serum and peritoneal fluid samples were potently angiogenic but there were no differences between open surgery and laparoscopy. Rates of tumour recurrence and survival were similar in the two groups. Conclusion: Despite differences in postoperative serum levels of IL-6 and VEGF after open and laparoscopic surgery in patients with colonic cancer, the angiogenic response is comparable in both surgical approaches. Registration number: ISRCTN55624793 (http://www.controlled-trials.com).
Role of polymorphonuclear cells in surgery-induced liver metastases development
2012
Surgical resection of primary colorectal tumors is currently the preferred and only treatment that can create long-term disease free survival. However, abdominal surgery caused increased tumor cell adhesion to the peritoneal wall or in the liver that grew out into metastases. Interestingly, depletion of PMNs diminished tumor recurrence, suggesting that PMNs might play a role in surgery-induced tumor development. Therefore, in the current study we investigated the role of PMNs in liver metastases formation. Increased levels of PMNs and tumor cells were observed in the livers of rats that underwent laparotomy, which were even higher in the livers of rats in which colonic resection was performed. As colectomy results in bacterial contamination, we next investigated the role of bacterial products in enhanced PMNs and tumor cell adhesion. Significantly more PMNs and tumor cells were observed in livers of rats that had been treated with the bacterial product lipopolysaccharide (LPS). More...
International Journal of Cancer, 2004
In this experimental study the influence of surgery-induced pro-inflammatory cytokines on tumour recurrence in the lung was investigated. A reproducible human in vitro assay was developed to study the adhesion of HT29 colon carcinoma cells to monolayers of microvascular endothelial cells of the lung (HMVEC-L) or human umbilical venous endothelial cells (HUVEC). Pre-incubation of HMVEC-L with maximally active concentrations of IL-1β and TNF-α, but not with IL-6, resulted in at least 250% adhesion compared to control adhesion (p≤0.01).
International Journal of Cancer, 2009
Interactions between endothelial selectins and selectin ligands expressed on tumor cells have been implicated in the binding of circulating metastatic cancer cells to the vascular endothelium during extravasation. Moreover, there is mounting evidence that inflammatory environments can accelerate the progression of metastasis by neutrophil mediated mechanisms. In this study, a physiologically relevant in vivo model of early metastasis coupled with intravital microscopy was used to visualize the trafficking of tumor cells within the liver vasculature in real time. Using GFPlabeled Lewis lung carcinoma subline H-59 cells, we show here that disrupting the interactions between endothelial selectins and tumor cell selectin ligands diminished tumor cell recruitment to the liver. Furthermore, systemic inflammation induced by intravenous injection of lipopolysaccharide significantly enhanced the metastatic potential of these lung carcinoma cells by increasing their propensity to adhere to the liver sinusoidal endothelium. Confocal microscopy revealed frequent colocalization of cancer cells with neutrophils and neutrophil depletion in vivo significantly attenuated the lipopolysaccharide-induced increase in H-59 cell adhesion. Although direct selectin-selectin ligand interactions contributed significantly to tumor cell adhesion to sinusoidal endothelial cells, we show here that in addition, interactions between adherent neutrophils within the inflamed sinusoids and circulating tumor cells may further increase tumor cell arrest in the liver. ' 2009 UICC Lung cancer is the leading cause of cancer-related deaths worldwide. 1 A high proportion of patients harbor metastasis to regional lymph nodes upon presentation, and over half of all patients who undergo curative intent surgical resection of the lung will develop metastatic recurrence. 2 The liver is a common site of metastasis for lung cancer, with autopsy studies showing hepatic metastases in over 50% of lung cancer patients. The hematogenous dissemination of cancer cells from a primary tumor to distant organs involves a cascade of sequential steps (reviewed in Refs. 4,. The adhesion of circulating tumor cells to the vascular endothelium of distant organs is a key step in the metastatic cascade that may determine the organ tropism and extent of metastasis. Interactions between endothelial selectins and tumor cell selectin ligands have been implicated in the metastatic process. 5-8 Selectins are a family of transmembrane glycoproteins possessing an extracellular lectin domain that binds to carbohydrate moieties present on their ligands. The three known selectins that function as cell adhesion molecules are expressed on the surface of endothelial cells (E-selectin and P-selectin), platelets (P-selectin) and leukocytes (L-selectin). E-selectin has been shown to contribute to the metastatic spread of multiple cancers, including lung and colon carcinoma, and melanoma. Functional inhibition of E-selectin has been shown to prevent adhesion of tumor cells to endothelial monolayers in vitro, and attenuate the development of metastases in vivo. In addition, L-selectin knockout mice were shown to develop fewer lung metastases following intravenous injection of colon carcinoma cells, implying that leukocyte selectin expression, and thus leukocyte-cancer cell interactions, may also play a role in the development of metastasis. The ligands recognized by selectins are fucosylated and sialylated carbohydrate antigens such as sialyl Lewis-a (sLe a ) and sialyl Lewis-x (sLe x ), which are present on mucin-like glycopro-teins. 13 sLe x and sLe a moieties are commonly found on the surface glycoproteins of metastatic cancer cells. 14 Numerous groups have reported a correlation between increased surface expression of sLe x on tumor cells, a higher rate of metastasis, and a worse prognosis suggesting that these glycoconjugates are functionally relevant to disease progression. 14,15 In vitro, down regulation of sLe x expression was found to reduce the capacity of tumor cells to adhere to vascular endothelial E-selectin. Although the impact of local inflammatory changes in the tumor microenvironment on metastases has been well documented (reviewed in Ref. 17), there is emerging evidence to suggest that systemic inflammation may influence the adhesion of circulating tumor cells in the microvasculature of distant organs and thereby metastasis. Investigating the role of systemic inflammation in lung cancer metastasis is highly relevant for several reasons. Surgical resection of the lung remains the cornerstone of any potentially curative treatment plan. However, this operative procedure is associated with surgical trauma resulting in significant systemic inflammation and increased cytokine release. In addition, high rates of postoperative complications accompany this procedure, with a bacterial pneumonia rate of 10-25% and increased systemic lipopolysaccharide release. 21,22 Several reports from clinical series have raised the possibility that inflammatory consequences resulting from postsurgical complications may influence cancer recurrence. Evidence from studies of other malignancies such as colorectal carcinoma have shown that proinflammatory cytokines such as TNFa and IL-1b increase tumor cell adhesion to endothelial cells in vitro and in vivo, largely by upregulating the expression of cell adhesion molecules such as selectins on the endothelial surface. In addition, soluble inflammatory mediators have been shown to increase the expression of selectin ligands on cancer cells. Finally, there is emerging evidence, primarily based on in vitro studies, that a third cellular participant, the neutrophil, may contribute to inflammation-facilitated cancer cell adhesion. 30-32 Together, these findings suggest that states of systemic inflammation may favor the development of metastases by augmenting the recruitment of circulating tumor cells into organ tissues. However, the role of systemic inflammation in the metastatic spread of lung carcinoma has not been adequately studied in vivo.