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: 4.6). 06/2007; 170(5):1781-92. DOI: 10.2353/ajpath.2007.060886
Source: PubMed

ABSTRACT 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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    ABSTRACT: Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-β, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-β1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, β1-integrin, calponin and α-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-β signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-β-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-β-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation.
    PLoS ONE 03/2015; 10(3):e0119655. DOI:10.1371/journal.pone.0119655 · 3.53 Impact Factor
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    ABSTRACT: Non alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the United States and worldwide. Our studies have previously shown an increase in metastatic burden in steatotic vs. normal livers using a mouse model of diet induced steatosis. In the present study we aim to identify and evaluate the molecular factors responsible for this increase in tumor burden. We assessed changes in expression of a panel of matrix metalloproteinases (MMPs) using qRT-PCR between normal and steatotic livers and validated them with western blot analysis of protein levels. To evaluate the role of MMP13 on tumor development, we utilized a splenic injection model of liver metastasis in Wildtype and Mmp13 deficient mice, using either parental or stable Mmp13 knockdown cell lines. Further, to evaluate changes in the ability of tumor cells to extravasate we utilized whole organ confocal microscopy to identify individual tumor cells relative to the vasculature. MTT, migration and invasion assays were performed to evaluate the role of tumor derived MMP13 on hallmarks of cancer in vitro. We found that MMP13 was significantly upregulated in the steatotic liver both in mice as well as human patients with NAFLD. We showed a decrease in metastatic tumor burden in Mmp13-/- mice compared to wildtype mice, explained in part by a reduction in the number of tumor cells extravasating from the hepatic vasculature in the Mmp13-/- mice compared to wildtype mice. Additionally, loss of tumor derived MMP13 through stable knockdown in tumor cell lines lead to decreased migratory and invasive properties in vitro and metastatic burden in vivo. This study demonstrates that stromal as well as tumor derived MMP13 contribute to tumor cell extravasation and establishment of metastases in the liver microenvironment.
    Molecular Cancer 02/2015; 14(1). DOI:10.1186/s12943-014-0282-0 · 5.40 Impact Factor
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    ABSTRACT: BACKGROUND Extravasation is a critical step in cancer metastasis, in which adhesion of intravascular cancer cells to the vascular endothelial cells is controlled by cell surface adhesion molecules. The role of interleukin-17 (IL-17), insulin, and insulin-like growth factor 1 (IGF1) in adhesion of prostate cancer cells to the vascular endothelial cells is unknown, which is the subject of the present study.METHODS Human umbilical vein endothelial cells (HUVECs) and human prostate cancer cell lines (PC-3, DU-145, LNCaP, and C4–2B) were analyzed for expression of vascular cell adhesion molecule 1 (VCAM-1), integrins, and cluster of differentiation 44 (CD44) using flow cytometry and Western blot analysis. The effects of IL-17, insulin, and IGF1 on VCAM-1 expression and adhesion of prostate cancer cells to HUVECs were examined. The interaction of VCAM-1 and CD44 was assessed using immunoprecipitation assays.RESULTSInsulin and IGF1 acted with IL-17 to increase VCAM-1 expression in HUVECs. PC-3, DU-145, LNCaP, and C4–2B cells expressed β1 integrin but not α4 integrin. CD44 was expressed by PC-3 and DU-145 cells but not by LNCaP or C4–2B cells. When HUVECs were treated with IL-17, insulin or IGF1, particularly with a combination of IL-17 and insulin (or IGF1), adhesion of PC-3 and DU-145 cells to HUVECs was significantly increased. In contrast, adhesion of LNCaP and C4–2B cells to HUVECs was not affected by treatment of HUVECs with IL-17 and/or insulin/IGF1. CD44 expressed in PC-3 cells physically bound to VCAM-1 expressed in HUVECs.CONCLUSIONSCD44-VCAM-1 interaction mediates the adhesion between prostate cancer cells and HUVECs. IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through increasing VCAM-1 expression in the vascular endothelial cells. These findings suggest that IL-17 may act with insulin/IGF1 to promote prostate cancer metastasis. Prostate © 2015 Wiley Periodicals, Inc.
    The Prostate 02/2015; DOI:10.1002/pros.22971 · 3.57 Impact Factor

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