Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments

Chronic stress is common among cancer patients due to the psychological, operative, or pharmaceutical stressors at the time of diagnosis or during the treatment of cancers. The continuous activations of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as results of chronic stress, have been demonstrated to take part in several cancer-promoting processes, such as tumorigenesis, progression, metastasis, and multi-drug resistance, by altering the tumor microenvironment (TME). Stressed TME is generally characterized by the increased proportion of cancer-promoting cells and cytokines, the reduction and malfunction of immune-supportive cells and cytokines, augmented angiogenesis, enhanced epithelial-mesenchymal transition, and damaged extracellular matrix. For the negative effects that these alterations can cause in terms of the efficacies of anti-cancer treatments and prognosis of patients, supplementary pharmacological or psychotherapeutic strategies targeting HPA, SNS, or psychological stress may be effective in improving the prognosis of cancer patients. Here, we review the characteristics and mechanisms of TME alterations under chronic stress, their influences on anti-cancer therapies, and accessory interventions and therapies for stressed cancer patients.

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Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature

Frontiers in Oncology ◽

10.3389/fonc.2020.612802 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 2

Author(s):

Aukie Hooglugt ◽

Miesje M. van der Stoel ◽

Reinier A. Boon ◽

Stephan Huveneers

Keyword(s):

Tumor Microenvironment ◽

Tumor Metastasis ◽

Lymphatic Vessels ◽

Cancer Therapies ◽

Tumor Cell Growth ◽

Vascular Normalization ◽

Cancer Treatments ◽

Anti Cancer ◽

Tumor Endothelium

Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.

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Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

10.1101/2020.04.29.068239 ◽

2020 ◽

Author(s):

Wen Jia ◽

Shubham Tripathi ◽

Priyanka Chakraborty ◽

Adithya Chedere ◽

Annapoorni Rangarajan ◽

...

Keyword(s):

Cell Division ◽

Epithelial Mesenchymal Transition ◽

Experimental Studies ◽

Therapy Resistance ◽

Cancer Therapies ◽

Mesenchymal Transition ◽

Anti Cancer ◽

Molecular Determinants ◽

Cancer Types ◽

Mesenchymal Epithelial Transition

AbstractEpithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

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CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

Cells ◽

10.3390/cells9071651 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1651

Author(s):

María Auxiliadora Olivares-Urbano ◽

Carmen Griñán-Lisón ◽

Juan Antonio Marchal ◽

María Isabel Núñez

Keyword(s):

Tumor Microenvironment ◽

Cancer Patients ◽

Epithelial Mesenchymal Transition ◽

Treatment Modalities ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Combination Strategies ◽

Technological Advances ◽

Oncologic Treatment ◽

The Impact

Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial–mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.

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Overcoming Chemoresistance via Extracellular Vesicle Inhibition

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.629874 ◽

2021 ◽

Vol 8 ◽

Author(s):

Raeesah Hayatudin ◽

Zhijack Fong ◽

Long Chiau Ming ◽

Bey-Hing Goh ◽

Wai-Leng Lee ◽

...

Keyword(s):

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Extracellular Vesicle ◽

Cancer Therapies ◽

Cancer Resistance ◽

Cancer Treatments ◽

Mesenchymal Transition ◽

Chemotherapy Drugs ◽

Research Activities

With the ever-growing number of cancer deaths worldwide, researchers have been working hard to identify the key reasons behind the failure of cancer therapies so the efficacy of those therapies may be improved. Based on extensive research activities and observations done by researchers, chemoresistance has been identified as a major contributor to the drastic number of deaths among cancer patients. Several factors have been linked to formation of chemoresistance, such as chemotherapy drug efflux, immunosuppression, and epithelial-mesenchymal transition (EMT). Lately, increasing evidence has shed light on the role of extracellular vesicles (EVs) in the regulation of chemoresistance. However, there is limited research into the possibility that inhibiting EV release or uptake in cancer cells may curb chemoresistance, allowing chemotherapy drugs to target cancer cells without restriction. Prominent inhibitors of EV uptake and release in cancer cells have been compiled and contrasted in this review. This is in the hope of sparking greater interest in the field of EV-mediated chemoresistance, as well as to provide an overview of the field for fundamental and clinical research communities, particularly in the field of cancer resistance research. In-depth studies of EV-mediated chemoresistance and EV inhibitors in cancer cells would spur significant improvement in cancer treatments which are currently available.

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Carotenoids in Cancer Metastasis—Status Quo and Outlook

Biomolecules ◽

10.3390/biom10121653 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1653

Author(s):

Lenka Koklesova ◽

Alena Liskova ◽

Marek Samec ◽

Kevin Zhai ◽

Mariam Abotaleb ◽

...

Keyword(s):

Cancer Patients ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Biological Activities ◽

Tissue Inhibitors Of Metalloproteinases ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Complex Process ◽

Anti Cancer

Metastasis represents a major obstacle in cancer treatment and the leading cause of cancer-related deaths. Therefore, the identification of compounds targeting the multi-step and complex process of metastasis could improve outcomes in the management of cancer patients. Carotenoids are naturally occurring pigments with a plethora of biological activities. Carotenoids exert a potent anti-cancer capacity in various cancer models in vitro and in vivo, mediated by the modulation of signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of the epithelial–mesenchymal transition and regulatory molecules, such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), urokinase plasminogen activator (uPA) and its receptor (uPAR), hypoxia-inducible factor-1α (HIF-1α), and others. Moreover, carotenoids modulate the expression of genes associated with cancer progression and inflammatory processes as key mediators of the complex process involved in metastasis. Nevertheless, due to the predominantly preclinical nature of the known anti-tumor effects of carotenoids, and unclear results from certain carotenoids in specific cancer types and/or specific parts of the population, a precise analysis of the anti-cancer effects of carotenoids is essential. The identification of carotenoids as effective compounds targeting the complex process of cancer progression could improve the outcomes of advanced cancer patients.

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Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment

Cancers ◽

10.3390/cancers12123801 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3801

Author(s):

Zhiyun Cao ◽

Nathaniel Weygant ◽

Parthasarathy Chandrakesan ◽

Courtney W. Houchen ◽

Jun Peng ◽

...

Keyword(s):

Tumor Microenvironment ◽

Epithelial Mesenchymal Transition ◽

Stem Cell Marker ◽

Biological Processes ◽

Cancer Stem Cell Marker ◽

Immune Microenvironment ◽

Mesenchymal Transition ◽

Anti Cancer ◽

Tumor Immune Microenvironment ◽

Small Molecular Inhibitors

Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.

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Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽

10.3390/cells10030558 ◽

2021 ◽

Vol 10 (3) ◽

pp. 558

Author(s):

Jin Kyung Seok ◽

Eun-Hee Hong ◽

Gabsik Yang ◽

Hye Eun Lee ◽

Sin-Eun Kim ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Autophagic Flux ◽

Oxidized Phospholipids ◽

Mcf7 Cells ◽

Mesenchymal Transition ◽

Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

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ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity

Cancers ◽

10.3390/cancers13061197 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1197

Author(s):

Julia Pohl ◽

Raluca-Ileana Mincu ◽

Simone M. Mrotzek ◽

Reza Wakili ◽

Amir A. Mahabadi ◽

...

Keyword(s):

High Risk ◽

Cancer Patients ◽

Left Ventricular ◽

Cardiac Biomarkers ◽

Cancer Therapies ◽

University Hospitals ◽

Anti Cancer ◽

Risk Patients ◽

Qrs Duration ◽

Ecg Score

Objective: To evaluate a new electrocardiographic (ECG) score reflecting domains of electrical and structural alterations in therapy-naïve cancer patients to assess their risk of cardiotoxicity. Methods: We performed a retrospective analysis of 134 therapy-naïve consecutive cancer patients in our two university hospitals concerning four ECG score parameters: Contiguous Q-waves, markers of left ventricular (LV) hypertrophy, QRS duration and JTc prolongation. Cardiotoxicity was assessed after a short-term follow-up (up to 12 months). Results: Of all the patients (n = 25), 19% reached 0 points, 50% (n = 67) reached 1 point, 25% (n = 33) reached 2 points, 5% (n = 7) reached 3 points and 0.7% reached 4 or 5 points (n = 1 respectively). The incidence of cardiotoxicity (n = 28 [21%]) increased with the ECG score, with 0 points at 0%, 1 point 7.5%, 2 points 55%, 3 points 71% and ≥3 points 50%. In the ROC (Receiver operating curves) analysis, the best cut-off for predicting cardiotoxicity was an ECG score of ≥2 points (sensitivity 82%, specificity 82%, AUC 0.84, 95% CI 0.77–0.92, p < 0.0001) which was then defined as a high-risk score. High-risk patients did not differ concerning their age, LV ejection fraction, classical cardiovascular risk factors or cardiac biomarkers compared to those with a low-risk ECG score. Conclusion: ECG scoring prior to the start of anti-cancer therapies may help to identify therapy-naïve cancer patients at a higher risk for the development of cardiotoxicity.

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