The Host Inflammatory Response Promotes Liver Metastasis by Increasing Tumor Cell Arrest and Extravasation

Department of Surgery, McGill University Health Cener and Royal Victoria Hospital, Quebec, Canada.
American Journal Of Pathology (Impact Factor: 4.59). 06/2007; 170(5):1781-92. DOI: 10.2353/ajpath.2007.060886
Source: PubMed


Inflammation can play a regulatory role in cancer progression and metastasis. Previously, we have shown that metastatic tumor cells entering the liver trigger a proinflammatory response involving Kupffer cell-mediated release of tumor necrosis factor-alpha and the up-regulation of vascular endothelial cell adhesion receptors, such as E-selectin. Here, we analyzed spatio-temporal aspects of the ensuing tumor-endothelial cell interaction using human colorectal carcinoma CX-1 and murine carcinoma H-59 cells and a combination of immunohistochemistry, confocal microscopy, and three-dimensional reconstruction. E-selectin expression was evident mainly on sinusoidal vessels by 6 and 10 hours, respectively, following H-59 and CX-1 inoculation, and this corresponded to a stabilization of the number of tumor cells within the sinuses. Tumor cells arrested in E-selectin(+) vessels and appeared to flatten and traverse the vessel lining, away from sites of intense E-selectin staining. This process was evident by 8 (H-59) and 12 (CX-1) hours after inoculation, coincided with increased endothelial vascular cell adhesion molecule-1 expression, and involved tumor cell attachment in areas of intense vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 expression. Nonmetastatic (human) MIP-101 and (murine) M-27 cells induced a weaker response and could not be seen to extravasate. The results show that metastatic tumor cells can alter the hepatic microvasculature and use newly expressed endothelial cell receptors to arrest and extravasate.

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Available from: Pnina Brodt, Apr 06, 2015
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    • "Furthermore, inflammation can play a regulatory role in cancer progression and metastasis. Metastatic tumor cells entering the liver trigger a proinflammatory response involving Kupffer cell-mediated release of TNF-α and the up-regulation of E-selectin in vascular endothelial cells [34]. In this study, we confirmed the adhesion of HBx-transfected cells to TNF-α-stimulated vascular endothelial cells using a monolayer cell adhesion assay. "
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    ABSTRACT: The metastasis of hematogenous cancer cells is associated with abnormal glycosylation such as sialyl lewis antigens. Although the hepatitis B virus X protein (HBx) plays important role in liver disease, the precise function of HBx on aberrant glycosylation for metastasis remains unclear. The human hepatocellular carcinoma tissues, HBx transgenic mice and HBx-transfected cells were used to check the correlation of expressions between HBx and Sialyl lewis antigen for cancer metastasis. To investigate whether expression levels of glycosyltransferases induced in HBx-transfected cells are specifically associated with sialyl lewis A (SLA) synthesis, which enhances metastasis by interaction of liver cancer cells with endothelial cells, ShRNA and siRNAs targeting specific glycosyltransferases were used. HBx expression in liver cancer region of HCC is associated with the specific synthesis of SLA. Furthermore, the SLA was specifically induced both in liver tissues from HBx-transgenic mice and in in vitro HBx-transfected cells. HBx increased transcription levels and activities of α2-3 sialyltransferases (ST3Gal III), α1-3/4 fucosyltransferases III and VII (FUT III and VII) genes, which were specific for SLA synthesis, allowing dramatic cell-cell adhesion for metastatic potential. Interestingly, HBx specifically induced expression of N-acetylglucosamine-β1-3 galactosyltransferase V (β1-3GalT 5) gene associated with the initial synthesis of sialyl lewis A, but not β1-4GalT I. The β1-3GalT 5 shRNA suppressed SLA expression by HBx, blocking the adhesion of HBx-transfected cells to the endothelial cells. Moreover, β1-3GalT 5 silencing suppressed lung metastasis of HBx-transfected cells in in vivo lung metastasis system. HBx targets the specific glycosyltransferases for the SLA synthesis and this process regulates hematogenous cancer cell adhesion to endothelial cells for cancer metastasis.
    Molecular Cancer 09/2014; 13(1):222. DOI:10.1186/1476-4598-13-222 · 4.26 Impact Factor
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    • "While the role of integrin in cancer progression is mainly associated with tumor cell invasion and tumor induced angiogenesis, integrins can play a direct role in tumor cell adhesion to the intravascular endothelium. For example, metastatic breast cancer cells deficient in integrin β1 expression fail to attach and transmigrate through the vessel endothelium [27] [53]. Furthermore, over-expression of neuropilin-2 non-kinase receptor (NPR-2) in cancer cells promotes successful attachment in an α5 integrin-dependent manner. "
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    ABSTRACT: Metastasis is the main cause of prostate cancer-associated deaths. While significant progress has been made in the treatment of primary tumors, efficient therapies that target the metastatic spread of prostate cancer are far from clinical reality. To efficiently treat cancer we need be able to impede its spread. Unfortunately, the majority of current therapeutics approved to treat metastatic cancer were originally selected based on their ability to inhibit primary tumor growth. This inherent flaw precludes these therapies from efficiently targeting the development of secondary metastatic lesions, a process that is distinct from that of primary tumor progression. In this review we will summarize the conceptual, cellular and molecular targets that should be considered to design effective anti-metastatic therapies.
    04/2014; 2(1):45-56.
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    • "In all cases reported of TC metastatic to oral cavity, the gingiva is affected. Some authors suggest the preference of metastasis to reach the attached gingiva in the presence of chronic gingivitis because the rich vascularity of the inflammatory process would allow trapping of tumour cells and thus being fertile site to spread most of the metastatic process (Auguste et al., 2007). Chronic inflammation is known to play a role in cancer initiation, promotion, and metastasis (Das Roy et al., 2012). "
    International Journal of Morphology 03/2013; 31(1):140-143. · 0.32 Impact Factor
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