scholarly journals Starvation and Climate Change—How to Constrain Cancer Cell Epigenetic Diversity and Adaptability to Enhance Treatment Efficacy

2021 ◽  
Vol 9 ◽  
Author(s):  
Christopher Gregg
Keyword(s):  
Tumor Cells ◽  
Metastatic Cancer ◽  
Epigenetic Mechanisms ◽  
Major Barrier ◽  
Adaptive Mechanisms ◽  
Cell Diversity ◽  
Treatment Paradigm ◽  
Epigenetic Diversity ◽  
Drug Treatments ◽  
The Many

Advanced metastatic cancer is currently not curable and the major barrier to eliminating the disease in patients is the resistance of subpopulations of tumor cells to drug treatments. These resistant subpopulations can arise stochastically among the billions of tumor cells in a patient or emerge over time during therapy due to adaptive mechanisms and the selective pressures of drug therapies. Epigenetic mechanisms play important roles in tumor cell diversity and adaptability, and are regulated by metabolic pathways. Here, I discuss knowledge from ecology, evolution, infectious disease, species extinction, metabolism and epigenetics to synthesize a roadmap to a clinically feasible approach to help homogenize tumor cells and, in combination with drug treatments, drive their extinction. Specifically, cycles of starvation and hyperthermia could help synchronize tumor cells and constrain epigenetic diversity and adaptability by limiting substrates and impairing the activity of chromatin modifying enzymes. Hyperthermia could also help prevent cancer cells from entering dangerous hibernation-like states. I propose steps to a treatment paradigm to help drive cancer extinction that builds on the successes of fasting, hyperthermia and immunotherapy and is achievable in patients. Finally, I highlight the many unknowns, opportunities for discovery and that stochastic gene and allele level epigenetic mechanisms pose a major barrier to cancer extinction that warrants deeper investigation.

scholarly journals Leveraging epigenetics to enhance the efficacy of immunotherapy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jonathan D. Licht ◽  
Richard L. Bennett
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Antigen Presentation ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Epigenetic Modifications ◽  
Main Body ◽  
Epigenetic Mechanisms

Abstract Background Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

scholarly journals Microfluidic Chip-Based Cancer Diagnosis and Prediction of Relapse by Detecting Circulating Tumor Cells and Circulating Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1385
Author(s):  
Hyeon-Yeol Cho ◽  
Jin-Ha Choi ◽  
Joungpyo Lim ◽  
Sang-Nam Lee ◽  
Jeong-Woo Choi
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Cancer ◽  
Cancer Prognosis ◽  
Optical Biosensors ◽  
Diagnosis And Prognosis ◽  
Noise Factors ◽  
Prediction Of Relapse

Detecting circulating tumor cells (CTCs) has been considered one of the best biomarkers in liquid biopsy for early diagnosis and prognosis monitoring in cancer. A major challenge of using CTCs is detecting extremely low-concentrated targets in the presence of high noise factors such as serum and hematopoietic cells. This review provides a selective overview of the recent progress in the design of microfluidic devices with optical sensing tools and their application in the detection and analysis of CTCs and their small malignant subset, circulating cancer stem cells (CCSCs). Moreover, discussion of novel strategies to analyze the differentiation of circulating cancer stem cells will contribute to an understanding of metastatic cancer, which can help clinicians to make a better assessment. We believe that the topic discussed in this review can provide brief guideline for the development of microfluidic-based optical biosensors in cancer prognosis monitoring and clinical applications.

Skin problems in palliative care

2019 ◽  
pp. 407-420
Keyword(s):  
Palliative Care ◽  
Wound Care ◽  
Metastatic Cancer ◽  
Physical Symptoms ◽  
Skin Involvement ◽  
Skin Disorders ◽  
Advanced Malignancy ◽  
Drug Treatments ◽  
Palliative Care Units

This chapter discusses skin disorders. Skin disorders affect patients with early and advanced malignant and non-malignant disease. In addition to distressing physical symptoms, the appearance of pressure sores, malignant wounds, and lymphoedema impact on patients’ social functioning, mood, and quality of life. Meticulous and prompt management of symptoms can make a huge difference. There is a growing body of research into drug treatments for pruritus in palliative care, and interventions for managing lymphoedema and wounds more effectively. Key principles in the management of wound care, lymphoedema, and pruritus are examined. Skin wounds are common in advanced malignancy. Pressure ulcers are most frequently seen, affecting an estimated one-third or more of patients in palliative care units. Malignant/fungating wounds occur in approximately 5–10% patients with metastatic cancer and are associated with significant physical and psychological distress. Loco-regional skin involvement (e.g. breast fungation) should be distinguished from generalized skin metastases which imply advanced disease.

Abstract A53: Epigenetic mechanisms of human chorionic gonadotropin (hCG) intracellular pathways activation in mammary tumor cells SKBR3

2013 ◽  
Author(s):  
Isidoro Binda-Neto ◽  
Silvana Aparecida Alves Correa-Noronha ◽  
Jorge Kede ◽  
Maria del Carmen GM Wolgien ◽  
Ismael DCG Silva ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Chorionic Gonadotropin ◽  
Mammary Tumor ◽  
Human Chorionic Gonadotropin ◽  
Epigenetic Mechanisms ◽  
Mammary Tumor Cells ◽  
Intracellular Pathways

scholarly journals Efficient Propagation of Circulating Tumor Cells: A First Step for Probing Tumor Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2784
Author(s):  
Jerry Xiao ◽  
Joseph R. McGill ◽  
Kelly Stanton ◽  
Joshua D. Kassner ◽  
Sujata Choudhury ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Cancer ◽  
Metastatic Breast ◽  
Success Rates ◽  
Breast Cancer Patients ◽  
Metastatic Cells ◽  
Healthy Donors

Circulating tumor cells (CTCs) represent a unique population of cells that can be used to investigate the mechanistic underpinnings of metastasis. Unfortunately, current technologies designed for the isolation and capture of CTCs are inefficient. Existing literature for in vitro CTC cultures report low (6−20%) success rates. Here, we describe a new method for the isolation and culture of CTCs. Once optimized, we employed the method on 12 individual metastatic breast cancer patients and successfully established CTC cultures from all 12 samples. We demonstrate that cells propagated were of breast and epithelial origin. RNA-sequencing and pathway analysis demonstrated that CTC cultures were distinct from cells obtained from healthy donors. Finally, we observed that CTC cultures that were associated with CD45+ leukocytes demonstrated higher viability. The presence of CD45+ leukocytes significantly enhanced culture survival and suggests a re-evaluation of the methods for CTC isolation and propagation. Routine access to CTCs is a valuable resource for identifying genetic and molecular markers of metastasis, personalizing the treatment of metastatic cancer patients and developing new therapeutics to selectively target metastatic cells.

A Case Illustrating That Cancer Tips the Scale of Thrombosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4128-4128
Author(s):  
Emma C. Scott ◽  
Jeffrey Cohn ◽  
Stephen Heitner
Keyword(s):  
Tumor Cells ◽  
Ductal Carcinoma ◽  
Metastatic Cancer ◽  
Factor V Leiden ◽  
Cysteine Proteases ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Patients With Cancer ◽  
Increased Risk ◽  
Prothrombin Mutation

Abstract Background: There are many causes of thrombosis in cancer, including cancer itself, the release of TNF, IL-1 &IL-6 causing endothelial damage, the interaction between tumor cells and macrophages activates platelets, factors X11 &X. Cysteine proteases &tissue factor, in the tumor cells have pro-coagulant activity (Bick, R. New Engl J of Med. Volume 349. July 2003). Chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of thrombosis. There is a RR of 4.1 for patients with cancer who did not have chemotherapy and 6.5 for patients with cancer who had chemotherapy (Heit et al. Arch Intern Med. 2000; 160: 809–815). Factor V Leiden mutation causes partial resistance to the inactivating effects of activated protein C. 5% of the population carries this mutation and it is present in 20% of patients with a 1st venous thrombotic episode. The risk of venous thrombosis is 3–8 fold. The prothrombin mutation is less common and the relative risk of thrombosis is about 2.0. In a large case control study it was found that carriers of the Factor V Leiden or the prothrombin mutation who also had cancer had an approximately 12–17 times increased risk of thrombosis; compared to an overall 7 times risk in patients with malignancy alone (Blom et al. JAMA. Feb 9, 2005. Vol 293, No 6). Case history: A 54 year old caucasion female was diagnosed with stage 1 infiltrating ductal carcinoma after palpating a lump in her left breast. The tumor was 1.6 cm, ER negative, PR negative and HER-2 negative. Lumpectomy and axillary node dissection revealed no residual carcinoma in the breast and no involvement of eleven lymph nodes. She completed 4 cycles of Cytoxan and Adriamycin successfully and was to start radiation therapy. 1 week after completing chemotherapy she had a focal seizure with tonicclonic movements of her right arm and no loss of consciousness. An MRI showed cortical infarcts, which were originally thought to be metastatic hemorrhages, in the left parietal and frontal areas and right parietal area. A follow up MRI showed considerable improvement of the cortical lesions, with no evidence of any metastatic cancer. Subsequently, she developed bilateral DVTs for which an IVC filter was placed as it was felt that she was not a candidate for anticoagulation given her recent CNS hemorrhage. She was also found to have bilateral pulmonary emboli on CT scan of the chest. Two other underlying disorders predisposing to thrombosis were found- Factor V Leiden mutation and the prothrombin gene mutation. Further imaging confirmed a thrombotic etiology for her CNS event, and coumadin was started. Conclusion: This case demonstrates the magnitude of the effect of cancer on thrombosis. This patient had 2 prothrombotic mutations, was a smoker, who had been on the OCP for 10 years prior to menopause, yet had no thrombotic episodes until she developed cancer. Also of interest is that the thrombotic episodes occurred shortly after completion of chemotherapy- another prothrombotic factor.

scholarly journals Microtube Device for Selectin-Mediated Capture of Viable Circulating Tumor Cells from Blood

2012 ◽  
Vol 58 (5) ◽  
pp. 846-853 ◽  
Author(s):  
Andrew D Hughes ◽  
Jeff Mattison ◽  
Laura T Western ◽  
John D Powderly ◽  
Bryan T Greene ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Cancer ◽  
Capture Rate ◽  
Buffy Coat ◽  
Cellular Damage ◽  
Cancer Therapies ◽  
Microscale Flow ◽  
Coated Surface ◽  
Personalized Cancer

Abstract BACKGROUND Circulating tumor cells (CTCs) can be used clinically to treat cancer. As a diagnostic tool, the CTC count can be used to follow disease progression, and as a treatment tool, CTCs can be used to rapidly develop personalized therapeutic strategies. To be effectively used, however, CTCs must be isolated at high purity without inflicting cellular damage. METHODS We designed a microscale flow device with a functionalized surface of E-selectin and antibody molecules against epithelial markers. The device was additionally enhanced with a halloysite nanotube coating. We created model samples in which a known number of labeled cancer cells were suspended in healthy whole blood to determine device capture efficiency. We then isolated and cultured primary CTCs from buffy coat samples of patients diagnosed with metastatic cancer. RESULTS Approximately 50% of CTCs were captured from model samples. Samples from 12 metastatic cancer patients and 8 healthy participants were processed in nanotube-coated or smooth devices to isolate CTCs. We isolated 20–704 viable CTCs per 3.75-mL sample, achieving purities of 18%–80% CTCs. The nanotube-coated surface significantly improved capture purities (P = 0.0004). Experiments suggested that this increase in purity was due to suppression of leukocyte spreading. CONCLUSIONS The device successfully isolates viable CTCs from both blood and buffy coat samples. The approximately 50% capture rate with purities >50% with the nanotube coating demonstrates the functionality of this device in a clinical setting and opens the door for personalized cancer therapies.

scholarly journals Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia

2021 ◽  
Author(s):  
Javier Garcia-Bermudez ◽  
Sheela Prasad ◽  
Lou Baudrier ◽  
Michael A. Badgley ◽  
Yuyang Liu ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pancreatic Tumor ◽  
Hypoxia Inducible Factor ◽  
Culture Conditions ◽  
Tumor Formation ◽  
High Plasticity ◽  
Hypoxic Conditions ◽  
Adaptive Mechanisms ◽  
Signaling Axis

ABSTRACTStress-adaptive mechanisms enable tumor cells to overcome metabolic constraints in nutrient and oxygen poor tumors. Aspartate is an endogenous metabolic limitation under hypoxic conditions, but the nature of the adaptive mechanisms that contribute to aspartate availability and hypoxic tumor growth are poorly understood. Here, using a combination of metabolomics and CRISPR-based genetic screens, we identify GOT2-catalyzed mitochondrial aspartate synthesis as an essential metabolic dependency for the proliferation of pancreatic tumor cells under hypoxic culture conditions. In contrast, GOT2-catalyzed aspartate synthesis is dispensable for pancreatic tumor formation in vivo. The dependence of pancreatic tumor cells on aspartate synthesis is bypassed in part by a hypoxia-induced potentiation of extracellular protein scavenging via macropinocytosis. This effect is mutant KRas-dependent, and is mediated by hypoxia inducible factor 1 (HIF1A) and its canonical target carbonic anhydrase-9 (CA9) through the cooption of the bicarbonate-macropinocytosis signaling axis. Our findings reveal high plasticity of aspartate metabolism and define an adaptive regulatory role for macropinocytosis by which mutant KRas tumors can overcome nutrient deprivation under hypoxic conditions.

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