Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrikines originate from the fragmentation of extracellular matrix proteins and regulate cellular activities by interacting with specific receptors. Matrikines are implicated in inflammation, immune responses, organ development, wound repair, angiogenesis, atherosclerosis, tumor progression and metastasis due to their ability to alter cellular migration, chemotaxis, and mitogenesis. Matrix metalloproteinases (MMPs) degrade extracellular matrix components under normal circumstances and in disease processes. Of the 20 MMPs identified, MMP-1, MMP-2, MMP-8, MMP-9, and MMP-12 have been implicated in regulating the matrikines Val-Gly-Val-Ala-Pro-Gly (elastin peptide) and proline-glycine-proline (PGP). Elastin peptide fragments are generated by elastolytic enzymes and have implications in atherosclerosis, neovascularization, chronic obstructive pulmonary disease, skin disease, as well as tumor invasion and spread. PGP is produced through a multistep pathway that liberates the tripeptide fragment from extracellular collagen. PGP is best described for its role in neutrophil chemotaxis and is implicated in the pathogenesis of corneal ulcers and in chronic lung conditions. In chronic cigarette smoke related lung disease, the PGP pathway can become a self-propagating cycle of inflammation through cigarette-smoke mediated inhibition of leukotriene A4 hydrolase, the enzyme responsible for degrading PGP and halting acute inflammation. This review highlights the roles of MMPs in generating these important matrikines.
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PMID:MMP generated matrikines. 2563 38

Eicosanoids, including PGs, produced by cyclooxygenases (COX), and leukotrienes, produced by 5-lipoxygenase (5-LO) have been implicated in cancer progression. These molecules are produced by both cancer cells and the tumor microenvironment (TME). We previously reported that both COX and 5-LO metabolites increase during progression in an orthotopic immunocompetent model of lung cancer. Although PGs in the TME have been well studied, less is known regarding 5-LO products produced by the TME. We examined the role of 5-LO in the TME using a model in which Lewis lung carcinoma cells are directly implanted into the lungs of syngeneic WT mice or mice globally deficient in 5-LO (5-LO-KO). Unexpectedly, primary tumor volume and liver metastases were increased in 5-LO-KO mice. This was associated with an ablation of leukotriene (LT) production, consistent with production mainly mediated by the microenvironment. Increased tumor progression was partially reproduced in global LTC4 synthase KO or mice transplanted with LTA4 hydrolase-deficient bone marrow. Tumor-bearing lungs of 5-LO-KO had decreased numbers of CD4 and CD8 T cells compared with WT controls, as well as fewer dendritic cells. This was associated with lower levels of CCL20 and CXL9, which have been implicated in dendritic and T cell recruitment. Depletion of CD8 cells increased tumor growth and eliminated the differences between WT and 5-LO mice. These data reveal an antitumorigenic role for 5-LO products in the microenvironment during lung cancer progression through regulation of T cells and suggest that caution should be used in targeting this pathway in lung cancer.
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PMID:Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment. 2666 81

Cancer progression is associated with the development of antitumor autoantibodies in patients' sera. Although passive treatment with antitumor antibodies has exhibited remarkable therapeutic efficacy, inhibitory effects on tumor progression by endogenous antitumor autoantibodies (EAAs) have been limited. In this study, we show that P4N, a derivative of the plant lignan nordihydroguaiaretic acid (NDGA), enhanced the production of EAAs and inhibited tumor growth at low noncytotoxic concentrations via its immunoregulatory activity. Intratumoral injection of P4N improved the quantity and quality of EAAs, and passive transfer of P4N-induced EAAs dramatically suppressed lung metastasis formation and prolonged the survival of mice inoculated with metastatic CT26 tumor cells. P4N-induced EAAs specifically recognized two surface antigens, 78-kDa glucose-regulated protein (GRP78) and F1F0 ATP synthase, on the plasma membrane of cancer cells. Additionally, P4N treatment led to B-cell proliferation, differentiation to plasma cells, and high titers of autoantibody production. By serial induction of autocrine and paracrine signals in monocytes, P4N increased B-cell proliferation and antibody production via the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway. This mechanism provides a useful platform for studying and seeking a novel immunomodulator that can be applied in targeting therapy by improving the quantity and quality of the EAAs.
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PMID:In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway. 2785 49

Cancer is the second leading cause of death worldwide and has become a global burden. It has long been known that inflammation is related to cancer, as inflammatory components have been identified in the tumor microenvironment and support tumor progression. Among the key inflammatory mediators, leukotrienes were found to be involved in cancer development. In particular, leukotriene B4, which is converted from leukotriene A4 by leukotriene A4 hydrolase (LTA4H), has been implicated in several types of cancer. In addition, LTA4H has attracted attention because of purported roles in inflammation and cancer development. Herein, we review the history of LTA4H, its emerging roles in cancer development, and the development of LTA4H inhibitors in cancer prevention and therapy.
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PMID:Leukotriene A4 hydrolase: an emerging target of natural products for cancer chemoprevention and chemotherapy. 3005 75