Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to develop predictive/prognostic markers for liver metastasis and recurrence following liver resection, investigating not only clinical parameters but also molecular markers that are known to be involved in the process of liver metastasis. Seventy colon cancer patients with either no distant metastasis (group A) or with resectable synchronous liver metastasis only (group B) were prospectively enrolled. All 70 patients received curative resection of the primary tumor. Group B patients underwent additional liver resection. Clinical parameters as well as serum levels of molecular markers [carcinoembryonic antigen (CEA), osteopontin, matrix metalloproteinase-7 (MMP-7), tissue inhibitor of metalloproteinase-1 (TIMP-1), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and E-selectin] from both tumor drainage (DV) and peripheral veins (PV) were analyzed. Results showed the clinical parameters were not significantly different between groups A and B. Nonetheless, the levels of VEGF and TIMP-1 from both DV and PV were significantly higher in group B compared to group A. In group A, 10 out of 33 (27.0%) patients developed metachronous liver metastasis. High levels of VEGF and TIMP-1 from DV were found to be significantly correlated with metachronous liver metastasis. In group B, 20 out of 33 (60.6%) patients had intrahepatic recurrence following resection of synchronous liver metastasis. The levels of VEGF from DV and the levels of TIMP-1 both from PV and DV were found to be significantly correlated with intrahepatic recurrence. Forty patients (7 from group A and 33 from group B) had liver resection and their 5-year disease-free survival rate was 15.9%. Univariate and multivariate analyses of prognostic factors revealed that the levels of VEGF and TIMP-1 from DV as well as the presence of lymph node metastasis from the primary tumor, synchronous metastasis and R1 resection were significantly associated with worse prognosis. The colon cancer patients with high levels of VEGF and TIMP-1 detected from the DV at the time of their initial surgery were found to have a high risk of metachronous liver metastasis and hepatic recurrence following the resection of synchronous liver metastasis. The high levels of VEGF and TIMP-1 were found to be significant predictive factors for poor prognosis following liver resection. These results require validation but pave the way for future transitional or clinical studies that may provide a greater understanding of colon cancer liver metastasis.
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PMID:High levels of serum VEGF and TIMP-1 are correlated with colon cancer liver metastasis and intrahepatic recurrence after liver resection. 2280 74

There is currently no effective means to prevent or control metastatic dissemination of cancer cells. E-selectin, an adhesion molecule expressed exclusively on inflamed and angiogenic blood vessels, plays an important role in several rate-limiting steps of cancer metastasis. In this study, we assessed the in vivo antitumor efficacy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers conjugated to an E-selectin binding peptide (Esbp, DITWDQLWDLMK) and equipped with the chemotherapeutic drug doxorubicin (P-(Esbp)-DOX) or with the proapoptotic peptide D(KLAKLAK)2 (P-(Esbp)-KLAK). Following a single intravenous injection, P-(Esbp)-DOX reduced tumor growth rate and prolonged the survival of mice bearing primary Lewis lung carcinoma (3LL) tumors significantly more than treatment with a non-targeted copolymer (P-DOX) or with free DOX. In an experimental B16-F10 lung metastasis model, a single intravenous dose of P-(Esbp)-DOX or P-(Esbp)-KLAK prolonged mice survival time significantly more than the non-targeted copolymers or the free drugs, and the percentage of complete tumor regression increased with increasing doses and with dosing frequency. In addition, mice pretreated with an E-selectin-targeted "drug-free" copolymer (P-(Esbp)-FITC) exhibited significantly fewer B16-F10 tumor foci in the lungs as compared with non-treated mice, demonstrating the anti-metastatic properties of the copolymer and its ability to control cancer spread through E-selectin-mediated interactions. Biodistribution analysis further confirmed the preferential accumulation of the E-selectin-targeted near-infrared fluorescently-labeled copolymer P-(Esbp)-IR783 in B16-F10 lung metastases. Taken together, this study demonstrates, for the first time, that the E-selectin targeted copolymer-drug conjugates can inhibit primary tumor growth and prevent metastases in vivo.
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PMID:Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer-drug conjugates. 2629 7

Polymer-drug conjugates that can actively target the tumor vasculature have emerged as an attractive technology for improving the therapeutic efficacy of cytotoxic drugs. We have recently provided, for the first time, in vivo evidence showing the significant advantage of the E-selectin-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate, P-(Esbp)-DOX, in inhibiting primary tumor growth and preventing the formation and development of cancer metastases. Here, we describe the design of a vascular endothelial growth factor receptor (VEGFR)-1-targeted HPMA copolymer-DOX conjugate (P-(F56)-DOX) that can actively and simultaneously target different cell types in the tumor microenvironment, such as endothelial cells (ECs), bone marrow-derived cells and many human cancer cells of diverse tumor origin. The VEGFR-1-targeted copolymer was tested for its binding, internalization and in vitro cytotoxicity in ECs (bEnd.3 and cEND cells) and cancer cells (B16-F10, 3LL and HT29). The in vivo anti-cancer activity of P-(F56)-DOX was then tested in two tumor-bearing mice (TBM) models (i.e., primary Lewis lung carcinoma (3LL) tumors and B16-F10 melanoma pulmonary metastases), relative to that of the E-selectin-targeted system (P-(Esbp)-DOX) that solely targets ECs. Our results indicate that the binding and internalization profiles of the VEGFR-1-targeted copolymer were superior towards ECs as compared to cancer cells and correlated well to the level of VEGFR-1 expression in cells. Accordingly, the VEGFR-1-targeted copolymer (P-(F56)-DOX) was more toxic towards bEnd.3 cells than to cancer cells, and exhibited significantly higher cytotoxicity than did the non-targeted control copolymer. P-(F56)-DOX inhibited 3LL tumor growth and significantly prolonged the survival of mice with B16-F10 pulmonary metastases. When compared to a system that actively targets only tumor vascular ECs, P-(F56)-DOX and P-(Esbp)-DOX exhibited comparable efficacy in slowing the growth of primary 3LL tumors and prolonging the survival of these mice. Still, P-(Esbp)-DOX had more pronounced anti-tumor activity in mice bearing B16-F10 lung metastases after a single intravenous injection, at an equivalent DOX dose. Overall, our results indicate that the VEGFR-1- and E-selectin-targeted drug delivery systems evaluated here show enhanced anti-cancer activity, and prolonged the survival of mice after a single intravenous injection. This is thus the first study comparing the anti-tumor activity of VEGFR-1- and E-selectin-targeted polymer drug conjugates in the same TBM models at an equivalent drug dose.
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PMID:Assessing the therapeutic efficacy of VEGFR-1-targeted polymer drug conjugates in mouse tumor models. 2700 92

Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficient mice show reduced metastasis, with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer cells and micrometastasis formation. Administration of E-selectin-neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.
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PMID:Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes. 2850 22

Surgical removal of the primary tumor is a common practice in breast cancer treatment. However, postsurgical metastasis poses an immense setback in cancer therapy. Considering that 90% of cancer-related deaths are due to metastasis, antimetastatic therapeutic strategies that can target disseminating tumor cells in the circulation before they can form secondary tumors hold preclinical and clinical potential for cancer patients. Our current work uses a liposomal formulation functionalized with the adhesion receptor E-selectin and the apoptosis-inducing ligand TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL) to reduce metastasis following tumor resection in an aggressive triple-negative breast cancer (TNBC) mouse model. We demonstrate that minimal administration of E-selectin-TRAIL liposomes can target metastasis in a TNBC model, with primary tumor resection to mimic clinical settings. Our study indicates that TRAIL liposomes, alone or in combination with existing clinically approved therapies, may neutralize distant metastasis of a broad range of tumor types systemically.
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PMID:Minimal dosing of leukocyte targeting TRAIL decreases triple-negative breast cancer metastasis following tumor resection. 3135 33


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