scholarly journals Cancer-Associated Thrombosis: Risk Factors, Molecular Mechanisms, Future Management

2020 ◽  
Vol 26 ◽  
pp. 107602962095428
Author(s):  
Marwa S. Hamza ◽  
Shaker A. Mousa
Keyword(s):  
Risk Factors ◽  
Thyroid Hormone ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Integrin Αvβ3 ◽  
Cancer Type ◽  
Major Health Problem ◽  
Patients With Cancer ◽  
Cancer Associated Thrombosis

Venous thromboembolism (VTE) is a major health problem in patients with cancer. Cancer augments thrombosis and causes cancer-associated thrombosis (CAT) and vice versa thrombosis amplifies cancer progression, termed thrombosis-associated cancer (TAC). Risk factors that lead to CAT and TAC include cancer type, chemotherapy, radiotherapy, hormonal therapy, anti-angiogenesis therapy, surgery, or supportive therapy with hematopoietic growth factors. There are some other factors that have an effect on CAT and TAC such as tissue factor, neutrophil extracellular traps (NETs) released in response to cancer, cancer procoagulant, and cytokines. Oncogenes, estrogen hormone, and thyroid hormone with its integrin αvβ3 receptor promote angiogenesis. Lastly, patient-related factors can play a role in development of thrombosis in cancer. Low-molecular-weight heparin and direct oral anticoagulants (DOACs) are used in VTE prophylaxis and treatment rather than vitamin K antagonist. Now, there are new directions for potential management of VTE in patients with cancer such as euthyroid, blockade of thyroid hormone receptor on integrin αvβ3, sulfated non-anticoagulant heparin, inhibition of NETs and stratifying low and high-risk patients with significant bleeding problems with DOACs.

scholarly journals Molecular Functions of Thyroid Hormone Signaling in Regulation of Cancer Progression and Anti-Apoptosis

2019 ◽  
Vol 20 (20) ◽  
pp. 4986 ◽  
Author(s):  
Yu-Chin Liu ◽  
Chau-Ting Yeh ◽  
Kwang-Huei Lin
Keyword(s):  
Cell Proliferation ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Integrin Αvβ3 ◽  
Cell Surface Receptor ◽  
Therapeutic Effects ◽  
Physiological Processes ◽  
Risk Of Cancer

Several physiological processes, including cellular growth, embryonic development, differentiation, metabolism and proliferation, are modulated by genomic and nongenomic actions of thyroid hormones (TH). Several intracellular and extracellular candidate proteins are regulated by THs. 3,3,5-Triiodo-L-thyronine (T3) can interact with nuclear thyroid hormone receptors (TR) to modulate transcriptional activities via thyroid hormone response elements (TRE) in the regulatory regions of target genes or bind receptor molecules showing no structural homology to TRs, such as the cell surface receptor site on integrin αvβ3. Additionally, L-thyroxine (T4) binding to integrin αvβ3 is reported to induce gene expression through initiating non-genomic actions, further influencing angiogenesis and cell proliferation. Notably, thyroid hormones not only regulate the physiological processes of normal cells but also stimulate cancer cell proliferation via dysregulation of molecular and signaling pathways. Clinical hypothyroidism is associated with delayed cancer growth. Conversely, hyperthyroidism is correlated with cancer prevalence in various tumor types, including breast, thyroid, lung, brain, liver and colorectal cancer. In specific types of cancer, both nuclear thyroid hormone receptor isoforms and those on the extracellular domain of integrin αvβ3 are high risk factors and considered potential therapeutic targets. In addition, thyroid hormone analogs showing substantial thyromimetic activity, including triiodothyroacetic acid (Triac), an acetic acid metabolite of T3, and tetraiodothyroacetic acid (Tetrac), a derivative of T4, have been shown to reduce risk of cancer progression, enhance therapeutic effects and suppress cancer recurrence. Here, we have reviewed recent studies focusing on the roles of THs and TRs in five cancer types and further discussed the potential therapeutic applications and underlying molecular mechanisms of THs.

scholarly journals Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

2001 ◽  
pp. 59-64 ◽  
Author(s):  
F Bogazzi ◽  
L Bartalena ◽  
S Brogioni ◽  
A Burelli ◽  
F Raggi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Molecular Level ◽  
Inhibitory Effect ◽  
Mobility Shift ◽  
Down Regulation ◽  
Nih3t3 Cells ◽  
Peripheral Tissues

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

scholarly journals PIWI-interacting RNAs and PIWI proteins in glioma: molecular pathogenesis and role as biomarkers

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Omid Reza Tamtaji ◽  
Mohammad Behnam ◽  
Mohammad Ali Pourattar ◽  
Michael R. Hamblin ◽  
Maryam Mahjoubin-Tehran ◽  
...  
Keyword(s):  
Risk Factors ◽  
Brain Tumor ◽  
Health Problem ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Epigenetic Mechanisms ◽  
Major Health Problem ◽  
Major Health ◽  
The World ◽  
Cellular Pathways

AbstractGlioma is the most common primary brain tumor, and is a major health problem throughout the world. Today, researchers have discovered many risk factors that are associated with the initiation and progression of gliomas. Studies have shown that PIWI-interacting RNAs (piRNAs) and PIWI proteins are involved in tumorigenesis by epigenetic mechanisms. Hence, it seems that piRNAs and PIWI proteins may be potential prognostic, diagnostic or therapeutic biomarkers in the treatment of glioma. Previous studies have demonstrated a relationship between piRNAs and PIWI proteins and some of the molecular and cellular pathways in glioma. Here, we summarize recent evidence and evaluate the molecular mechanisms by which piRNAs and PIWI proteins are involved in glioma.

scholarly journals Chemically-Modified Tetraiodothyroacetic Acid (Tetrac) Induces Cancer Cell Apoptosis and Facilitates Clearance of Apoptotic Debris (Efferocytosis)

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1012-A1013
Author(s):  
Kavitha Godugu ◽  
Hung-yun Lin ◽  
Shaker A Mousa ◽  
Paul J Davis
Keyword(s):  
Thyroid Hormone ◽  
Drug Treatment ◽  
Tumor Cell ◽  
Molecular Mechanisms ◽  
Integrin Αvβ3 ◽  
Hormone Analogue ◽  
Human Glioblastoma ◽  
Chemically Modified ◽  
End Of Treatment ◽  
Apoptotic Change

Abstract Tetraiodothyroaetic acid (tetrac) is a derivative of L-thyroxine with anticancer properties. By multiple molecular mechanisms, tetrac and chemically-modified tetrac induce apoptosis in a variety of human cancer cells in vitro and in xenografts. The anticancer activities of tetrac are initiated at the thyroid hormone analogue receptor on the extracellular domain of plasma membrane integrin αvβ3 (PJ Davis et al., Physiol Rev 101:319-352, 2021). Induction of apoptosis in glioblastoma xenograft with chemically modified tetrac (P-bi-TAT) has yielded 90% in volume of grafts that continues after discontinuation of tetrac. In the present study, we show that human glioblastoma xenograft shrinkage in response to P-bi-TAT is associated with local appearance of phagocytic monocytes and clearance of apoptotic debris (efferocytosis). Primary culture xenograft of glioblastoma cells (GBM 052814, kindly provided by the University of Pittsburgh Medical Center, Department of Neurosurgery) and U87-luc (ATCC, Manassas, VA) xenografts were generated in 5-member groups of nude mice for each tumor cell type and for controls. Five days post-implantation, injection of animals was begun with PBS (control) or P-bi-TAT (10 mg/kg body weight). Injection was continued X21 days and animals were then maintained off-treatment for an additional 21 days. Tumors were harvested, formalin-fixed and slide-mounted, then analyzed by TUNEL assay for apoptosis and by anti-CD68 staining for monocytic macrophage content. Histologic analysis (H&E staining) was also carried out. TUNEL analysis and histopathology of both xenograft models revealed more than 90% apoptotic change with 21-days of P-bi-TAT treatment (P <0.001) and persistence of 40% apoptotic change 3 weeks post-discontinuation of drug (P<0.001 vs. end of treatment change). By H&E histology and CD68 analysis, monocytes accounted for more than 90% of the viable cells after 3 weeks’ drug treatment. Sixty percent of the end-of-treatment monocyte population persisted 3 weeks after discontinuation of P-bi-TAT (P <0.001). Histology revealed negligible cell debris after 3 weeks of drug treatment and at 3 weeks post-discontinuation of P-bi-TAT. Thus, the anticancer/pro-apoptotic action of tetrac-containing P-bi-TAT is associated with efferocytosis that contributes to the frank tumor shrinkage that results from P-bi-TAT treatment of human glioblastoma xenografts. This is the first documentation of efferocytosis regulated from the thyroid hormone analogue receptor on tumor cell integrin αvβ3.

scholarly journals Six1 promotes skeletal muscle thyroid hormone response through regulation of the MCT10 transporter

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
John Girgis ◽  
Dabo Yang ◽  
Imane Chakroun ◽  
Yubing Liu ◽  
Alexandre Blais
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Tibialis Anterior ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Muscle Metabolism ◽  
Loss Of Function ◽  
Fast Twitch Muscle ◽  
Fast Twitch

Abstract Background The Six1 transcription factor is implicated in controlling the development of several tissue types, notably skeletal muscle. Six1 also contributes to muscle metabolism and its activity is associated with the fast-twitch, glycolytic phenotype. Six1 regulates the expression of certain genes of the fast muscle program by directly stimulating their transcription or indirectly acting through a long non-coding RNA. We hypothesized that additional mechanisms of action of Six1 might be at play. Methods A combined analysis of gene expression profiling and genome-wide location analysis data was performed. Results were validated using in vivo RNA interference loss-of-function assays followed by measurement of gene expression by RT-PCR and transcriptional reporter assays. Results The Slc16a10 gene, encoding the thyroid hormone transmembrane transporter MCT10, was identified as a gene with a transcriptional enhancer directly bound by Six1 and requiring Six1 activity for full expression in adult mouse tibialis anterior, a predominantly fast-twitch muscle. Of the various thyroid hormone transporters, MCT10 mRNA was found to be the most abundant in skeletal muscle, and to have a stronger expression in fast-twitch compared to slow-twitch muscle groups. Loss-of-function of MCT10 in the tibialis anterior recapitulated the effect of Six1 on the expression of fast-twitch muscle genes and led to lower activity of a thyroid hormone receptor-dependent reporter gene. Conclusions These results shed light on the molecular mechanisms controlling the tissue expression profile of MCT10 and identify modulation of the thyroid hormone signaling pathway as an additional mechanism by which Six1 influences skeletal muscle metabolism.

scholarly journals The Incidence of Cancer Associated Thrombosis is Increasing Over Time

2021 ◽  
Author(s):  
Anjlee Mahajan ◽  
Ann Brunson ◽  
Oyebimpe Adesina ◽  
Theresa HM Keegan ◽  
Ted Wun
Keyword(s):  
Risk Factors ◽  
Cumulative Incidence ◽  
Temporal Trends ◽  
Individual Risk ◽  
Cancer Type ◽  
Tumor Type ◽  
Risk Of Death ◽  
Breast And Prostate Cancer ◽  
Cancer Associated Thrombosis ◽  
Over Time

Cancer associated thrombosis (CAT) is an important cause of morbidity and mortality for patients with malignancy and varies by primary cancer type, stage and therapy. We aimed to characterize the incidence, risk factors, temporal trends and the effect on mortality of CAT. The California Cancer Registry was linked to the statewide hospitalization database to identify individuals with the 13 most common malignancies diagnosed 2005 -2017 and determine the 6 and 12-month cumulative incidence of CAT by venous thromboembolism (VTE) location, tumor type and stage after adjusting for competing risk of death. Cox proportional hazard regression models were used to determine risk factors associated with CAT and the effect of CAT on all-cause mortality. 942,019 patients with cancer were identified; 62,003 (6.6%) had an incident diagnosis of CAT. Patients with pancreatic, brain, ovarian, and lung cancer had the highest and patients with breast and prostate cancer had the lowest 12-month cumulative incidence of CAT. For most malignancies, men, those with metastatic disease and more co-morbidities, and African-Americans (vs. non-Hispanic Whites) were at highest risk for CAT. Patients diagnosed with cancer 2014-2017 had higher risk of CAT compared to those diagnosed 2005-2007. CAT was associated with increased overall mortality for all malignancies (HR ranges 1.89 - 4.79). The incidence of CAT increased over time and was driven by an increase in PE±DVT. CAT incidence varies based on tumor type and stage, and on individual risk factors including gender, race/ethnicity, and co-morbidities. For all tumor types CAT is associated with an increased mortality.

Cancer-Associated Thrombosis: A Two-Way Street

2019 ◽  
Vol 45 (06) ◽  
pp. 559-568 ◽  
Author(s):  
Bal Krishan Sharma ◽  
Matthew J. Flick ◽  
Joseph S. Palumbo
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Cancer Pathogenesis ◽  
Bidirectional Relationship ◽  
Clotting Cascade ◽  
Tumor Growth And Metastasis ◽  
Cancer Associated Thrombosis

AbstractPathological activation of the coagulation system occurs with virtually all forms of cancer, particularly epithelial malignancies. Accordingly, thrombosis is one of the most common comorbidities associated with cancer. Indeed, cancer-associated thromboembolism is the second leading cause of death for cancer patients, second only to the cancer itself. The identification of specific molecular mechanisms whereby tumor cells activate the coagulation system and drive thrombosis has been an active area of investigation for several decades. Studies in animal models and human trials have revealed that there is a bidirectional relationship between coagulation factor activity and cancer, whereby the pathological hemostatic system activation associated with cancer not only promotes thromboembolism but also drives progression of the malignancy. Numerous studies indicate that factors up and down the clotting cascade can contribute to various stages of cancer, including tumorigenesis, primary tumor growth, and metastasis. Although there are some mechanistic points of commonality, there are also clearly context-dependent contributions of coagulation components to cancer progression dependent on the type of cancer and stage of disease. It is also notable that in some instances, coagulation factors appear to contribute to cancer progression independently of their traditional roles in hemostasis and thrombosis. Here, the authors review the current state of the field with regard to hemostatic factor-driven cancer pathogenesis.

Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor

2009 ◽  
Vol 297 (6) ◽  
pp. E1238-E1246 ◽  
Author(s):  
Paul J. Davis ◽  
Faith B. Davis ◽  
Hung-Yun Lin ◽  
Shaker A. Mousa ◽  
Min Zhou ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cell Surface ◽  
Tumor Cell ◽  
Cell Biology ◽  
Thyroid Hormone Receptor ◽  
Integrin Αvβ3 ◽  
Integrin Receptor ◽  
Cell Functions ◽  
Mediated Effects ◽  
Hormone Analogs

A thyroid hormone receptor on integrin αvβ3 that mediates cell surface-initiated nongenomic actions of thyroid hormone on tumor cell proliferation and on angiogenesis has been described. Transduction of the hormone signal into these recently recognized proliferative effects is by extracellular-regulated kinases 1/2 (ERK1/2). Other nongenomic actions of the hormone may be transduced by phosphatidylinositol 3-kinase (PI3K) and are initiated in cytoplasm or at the cell surface. PI3K-mediated effects are important to angiogenesis or other recently appreciated cell functions but apparently not to tumor cell division. For those actions of thyroid hormone [l-thyroxine (T4) and 3,3′-5-triiodo-l-thyronine (T3)] that begin at the integrin receptor, tetraiodothyroacetic acid (tetrac) is an inhibitor of and probe for the participation of the receptor in downstream intracellular events. In addition, tetrac has actions initiated at the integrin receptor that are unrelated to inhibition of the effects of T4 and T3 but do involve gene transcription in tumor cells. Discussed here are the implications of translating these nongenomic mechanisms of thyroid hormone analogs into clinical cancer cell biology, tumor-related angiogenesis, and modulation of angiogenesis that is not related to cancer.

scholarly journals Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment

2021 ◽  
Vol 22 (8) ◽  
pp. 4112
Author(s):  
Silvia Triarico ◽  
Alberto Romano ◽  
Giorgio Attinà ◽  
Michele Antonio Capozza ◽  
Palma Maurizi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Molecular Mechanisms ◽  
Pediatric Patients ◽  
Common Side Effect ◽  
Peripheral Neurotoxicity ◽  
Dose Time ◽  
Patients With Cancer ◽  
Pain Disability ◽  
Related Risk ◽  
Oncologic Patients

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug–drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.

Estimating Bleeding Risk in Patients with Cancer-Associated Thrombosis: Evaluation of Existing Risk Scores and Development of a New Risk Score

2021 ◽  
Author(s):  
Maria A. de Winter ◽  
Jannick A. N. Dorresteijn ◽  
Walter Ageno ◽  
Cihan Ay ◽  
Jan Beyer-Westendorf ◽  
...  
Keyword(s):  
Prediction Model ◽  
External Validation ◽  
Predictive Performance ◽  
Bleeding Risk ◽  
Risk Scores ◽  
Cancer Type ◽  
Clinical Predictors ◽  
Internal Validation ◽  
Patients With Cancer ◽  
Cancer Associated Thrombosis

Abstract Background Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice. Objectives To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model. Methods In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event (“CAT-BLEED”). Results Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50–0.57; poor calibration). Internal validation of the pragmatic classification and “CAT-BLEED” showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56–0.66, and 0.63; 95% CI 0.58–0.68; good calibration). Conclusion Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with “CAT-BLEED,” but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated.

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