Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A loss of stromal Cav-1 in the tumor fibroblast compartment is associated with early tumor recurrence, lymph-node metastasis, and tamoxifen-resistance, resulting in poor clinical outcome in breast cancer patients. Here, we have used Cav-1 (-/-) null mice as a pre-clinical model for this "lethal tumor micro-environment." Metabolic profiling of Cav-1 (-/-) mammary fat pads revealed the upregulation of numerous metabolites (nearly 100), indicative of a major catabolic phenotype. Our results are consistent with the induction of oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy. The two most prominent metabolites that emerged from this analysis were ADMA (asymmetric dimethyl arginine) and BHB (beta-hydroxybutyrate; a ketone body), which are markers of oxidative stress and mitochondrial dysfunction, respectively. Transcriptional profiling of Cav-1 (-/-) stromal cells and human tumor stroma from breast cancer patients directly supported an association with oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy, as well as ADMA and ketone production. MircoRNA profiling of Cav-1 (-/-) stromal cells revealed the upregulation of two key cancer-related miR's, namely miR-31 and miR-34c. Consistent with our metabolic findings, these miR's are associated with oxidative stress (miR-34c) or activation of the hypoxic response/HIF1a (miR-31), which is sufficient to drive authophagy/mitophagy. Thus, via an unbiased comprehensive analysis of a lethal tumor micro-environment, we have identified a number of candidate biomarkers (ADMA, ketones, and miR-31/34c) that could be used to identify high-risk cancer patients at diagnosis, for treatment stratification and/or for evaluating therapeutic efficacy during anti-cancer therapy. We propose that the levels of these key biomarkers (ADMA, ketones/BHB, miR-31, and miR-34c) could be (1) assayed using serum or plasma from cancer patients, or (2) performed directly on excised tumor tissue. Importantly, induction of oxidative stress and autophagy/mitophagy in the tumor stromal compartment provides a means by which epithelial cancer cells can directly "feed off" of stromal-derived essential nutrients, chemical building blocks (amino acids, nucleotides), and energy-rich metabolites (glutamine, pyruvate, ketones/BHB), driving tumor progression and metastasis. Essentially, aggressive cancer cells are "eating" the cancer-associated fibroblasts via autophagy/mitophagy in the tumor micro-environment. Lastly, we discuss that this "Autophagic Tumor Stroma Model of Cancer Metabolism" provides a viable solution to the "Autophagy Paradox" in cancer etiology and chemo-therapy.
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PMID:The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. 2086 72

We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the "Reverse Warburg Effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly assess the prognostic value of the "Reverse Warburg Effect." MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (< 18% survival at 10 y post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-y survival rates of ~97% (p-value < 10 (-32) ). High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 10 (-14) ), a known marker of early tumor recurrence and metastasis. In fact, the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the "conventional" Warburg effect does not predict clinical outcome. Thus, the "Reverse Warburg Effect" or "parasitic" energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such as, AR-C155858, AR-C117977, and AZD-3965).
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PMID:Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. 2254 77

Trousseau's syndrome (cancer-associated thrombosis) is the second leading cause of death in cancer patients, after death from cancer itself. The risk of a venous thromboembolism is 4- to 7-fold higher in patients with cancer than in those without cancer. The causes of this impaired coagulation are associated with general patient-related risk factors, and other factors that are specific to the particular cancer or treatment. It is important to assess the risk of thrombotic events in cancer patients and administer effective prophylaxis and treatment. Effective prophylaxis and treatment of venous thromboembolism reduces morbidity and mortality, and improves patients' quality of life. Low molecular weight heparin is the first-line treatment for venous thromboembolism, as an effective and safe means for prophylaxis and treatment, according to guidelines released by international scientific societies. Oral anticoagulation therapy with warfarin is preferable to no therapy. However, warfarin has low efficacy and is associated with high rates of recurrence. If low molecular weight heparin is unavailable, some guidelines recommend the use of vitamin K antagonists that have a target international normalized ratio in the range of 2-3, as acceptable alternatives. Novel oral anticoagulants that directly inhibit factor Xa or thrombin are promising for the prophylaxis of high-risk cancer patients and in the long-term treatment of venous thromboembolism. However, to date, there is insufficient evidence to support the use of these new anticoagulants.
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PMID:Trousseau's syndrome: cancer-associated thrombosis. 2654 90

Venous thromboembolism (VTE) is a common complication of cancer occurring in up to one-fifth of cancer patients. The risk of VTE, which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), is increased up to seven-fold in patients with cancer. While the indications and contraindications to treatment for VTE patients with cancer parallel to those patients without cancer, the treatment of VTE is challenging for cancer patients who are three-fold more likely to have VTE recurrence than patients without cancer and who are also at increased risk of bleeding. While anticoagulant therapy is recommended for most cancer patients with VTE, some patients may benefit from alternative interventions, such as thrombolysis, thromboembolectomy, or placement of an inferior vena cava (IVC) filter. Recent data support the use of direct oral anticoagulants (DOACs) for treatment of cancer-associated VTE in select cancer patients and for primary prevention of thromboembolism in high-risk cancer patients. Individualized decision-making, keeping in consideration the patient's risk for thrombotic and bleeding events is essential.
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PMID:Risks and Benefits of Anticoagulation in Cancer and Noncancer Patients. 3135 Jul 35

The American Society of Clinical Oncology (ASCO) recently updated their clinical practice guidelines. The most novel aspect of this update is represented by the introduction of DOACs as pharmacological options both for prophylaxis and treatment of VTE in patients with cancer. The heterogeneity of the cancer population in terms of type and stage of the malignancy, presence of comorbidities, and variability in cancer treatments and prognosis represent the major challenge of managing VTE in patients with cancer. The use of VTE prophylaxis is currently recommended in cancer patients admitted to the hospital for an acute illness or reduced mobility, but no sufficient information is available on the risk of bleeding during thromboprophylaxis. Concerning the thromboprophylaxis in ambulatory cancer patients receiving chemotherapy, further refinement of existing risk models or development of new models are needed for improving risk stratification to identify high-risk cancer patients. The updated ASCO guidelines recommend the use of DOACs (edoxaban and rivaroxaban) for treatment of VTE in patients with cancer. However, Major concerns on "real-life" use of DOACs in patients with cancer are highlighted especially for the bleeding risk in patients with gastrointestinal cancers and the potential drug-drug interactions with specific anticancer therapies. CONCLUSIONS: Uncertainties to the updated ASCO guidelines remain concerning a number of indications on prophylaxis and treatment due to the limited evidence available. These limitations determine the low strength of the recommendations. The ongoing studies will contribute to refine the best management of patients with cancer-associated VTE.
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PMID:Management of venous thromboembolism in cancer patients: Considerations about the clinical practice guideline update of the American society of clinical oncology. 3173 52

Cancer patients have an increased risk of venous thromboembolism (VTE). The rate of VTE varies with cancer type, with pancreatic cancer having one of the highest rates, suggesting that there are cancer type-specific mechanisms of VTE. Risk assessment scores, such as the Khorana score, have been developed to identify ambulatory cancer patients at high risk of VTE. However, the Khorana score performed poorly in discriminating pancreatic cancer patients at risk of VTE. Currently, thromboprophylaxis is not recommended for cancer outpatients. Recent clinical trials showed that factor Xa (FXa) inhibitors reduced VTE in high-risk cancer patients but also increased major bleeding. Understanding the mechanisms of cancer-associated thrombosis should lead to the development of safer antithrombotic drugs. Mouse models can be used to study the role of different prothrombotic pathways in cancer-associated thrombosis. Human and mouse studies support the notion that 2 prothrombotic pathways contribute to VTE in pancreatic cancer patients: tumor-derived, tissue factor-positive (TF+) extracellular vesicles (EVs), and neutrophils and neutrophil extracellular traps (NETs). In pancreatic cancer patients, elevated levels of plasma EVTF activity and citrullinated histone H3 (H3Cit), a NET biomarker, are independently associated with VTE. We observed increased levels of circulating tumor-derived TF+ EVs, neutrophils, cell-free DNA, and H3Cit in nude mice bearing human pancreatic tumors. Importantly, inhibition of tumor-derived human TF, depletion of neutrophils, or administration of DNAse I to degrade cell-free DNA (including NETs) reduced venous thrombosis in tumor-bearing mice. These studies demonstrate that tumor-derived TF+ EVs, neutrophils, and cell-free DNA contribute to venous thrombosis in a mouse model of pancreatic cancer.
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PMID:Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models. 3180 71

HOXB13 p.Gly84Glu is recognized as a rare variant associated with increased risk for prostate cancer; risk association for other cancers is uncertain. This HOXB13 variant was originally reported in several 3-generation prostate cancer pedigrees and has been reported to be associated with increased risk for bladder and colorectal cancer and leukemia in GWAS. A HOXB13 pGly84Glu variant carrier was identified in a set of Utah individuals born more than 100 years ago who were members of high-risk cancer pedigrees. The proband carrier was diagnosed with colon cancer and is a member of a high-risk prostate cancer pedigree. The HOXB13 pGLY84Glu variant was assayed in other sampled relatives in the pedigree and was observed to segregate in relatives of the proband carrier in the extended pedigree; this pedigree showed significant excess of prostate cancer, cervical cancer, leukemia, colorectal cancer, and gastric cancer among descendants. Multiple additional variant carriers were identified, diagnosed with prostate, bladder, and colon cancers in the 5-generation high-risk cancer pedigree. This study shows the power and efficiency of a biorepository of samples with known genealogy from extended high-risk pedigrees for definition of cancer-associated risks. Association of HOXB13 p.Gly84Glu with risk of colon and bladder cancers in this extended pedigree confirms previous reports for risk association for both cancers.
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PMID:The HOXB13 p.Gly84Glu variant observed in an extended five generation high-risk prostate cancer pedigree supports risk association for multiple cancer sites. 3309 13