Impact of cancer metabolism on therapy resistance - Clinical implications

2021 ◽  
pp. 100797
Author(s):  
Ana Cristina Gonçalves ◽  
Elena Richiardone ◽  
Joana Jorge ◽  
Bárbara Polónia ◽  
Cristina P.R. Xavier ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Therapy Resistance ◽  
Clinical Implications

scholarly journals Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea Chisari ◽  
Irene Golán ◽  
Sabrina Campisano ◽  
Caroline Gélabert ◽  
Aristidis Moustakas ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cancer Metabolism ◽  
Redox Balance ◽  
Therapy Resistance ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Term Survival ◽  
Aggressive Cancer ◽  
Cancer Types ◽  
Tumor Types

Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

scholarly journals Extracellular citrate and metabolic adaptations of cancer cells

2021 ◽  
Author(s):  
E. Kenneth Parkinson ◽  
Jerzy Adamski ◽  
Grit Zahn ◽  
Andreas Gaumann ◽  
Fabian Flores-Borja ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Immune Cells ◽  
Warburg Effect ◽  
Cancer Metabolism ◽  
Krebs Cycle ◽  
Therapy Resistance ◽  
Tumour Microenvironment ◽  
The Warburg Effect

Abstract It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

scholarly journals Cancer Metabolism and the Evasion of Apoptotic Cell Death

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1144 ◽  
Author(s):  
Aditi Sharma ◽  
Lawrence H. Boise ◽  
Mala Shanmugam
Keyword(s):  
Cell Death ◽  
Cancer Metabolism ◽  
Apoptotic Cell ◽  
Therapy Resistance ◽  
Nutrient Acquisition ◽  
Cellular Growth ◽  
Cancer Hallmarks ◽  
Primary Focus ◽  
Multicellular Organisms ◽  
Energy Dependent

Cellular growth and proliferation depend upon the acquisition and synthesis of specific metabolites. These metabolites fuel the bioenergy, biosynthesis, and redox potential required for duplication of cellular biomass. Multicellular organisms maintain tissue homeostasis by balancing signals promoting proliferation and removal of cells via apoptosis. While apoptosis is in itself an energy dependent process activated by intrinsic and extrinsic signals, whether specific nutrient acquisition (elevated or suppressed) and their metabolism regulates apoptosis is less well investigated. Normal cellular metabolism is regulated by lineage specific intrinsic features and microenvironment driven extrinsic features. In the context of cancer, genetic abnormalities, unconventional microenvironments and/or therapy engage constitutive pro-survival signaling to re-program and rewire metabolism to maintain survival, growth, and proliferation. It thus becomes particularly relevant to understand whether altered nutrient acquisition and metabolism in cancer can also contribute to the evasion of apoptosis and consequently therapy resistance. Our review attempts to dissect a causal relationship between two cancer hallmarks, i.e., deregulated cellular energetics and the evasion of programmed cell death with primary focus on the intrinsic pathway of apoptosis.

scholarly journals Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3762
Author(s):  
Melissa Schwab ◽  
Katharina Thunborg ◽  
Omid Azimzadeh ◽  
Christine von Toerne ◽  
Caroline Werner ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Metabolism ◽  
Glucose Deprivation ◽  
Therapy Resistance ◽  
Hsp70 Expression ◽  
Heat Shock Factor 1 ◽  
Double Knockout ◽  
Ldh Activity

The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH−/−) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.

scholarly journals OR05-04 Steroid Receptor Co-Activators Complexes Cooperate with Progesterone Receptors (PR) to Reprogram Metabolic Pathways that Drive Therapy Resistant Populations in ER+ Breast Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Thu H Truong ◽  
Elizabeth Benner ◽  
Julie Hanson Ostrander ◽  
Carol A Lange
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Tumor Cell ◽  
Cell Biology ◽  
Cancer Metabolism ◽  
Progesterone Receptors ◽  
Steroid Receptor ◽  
Therapy Resistance ◽  
Cell Populations ◽  
Minority Population

Abstract Late recurrence of metastatic disease stemming from acquired therapy resistance remains a significant health burden for women with ER+ breast cancer. Disseminated ER+ tumor cell populations can remain quiescent for years to decades, and contributing factors include breast cancer stem cells (CSCs), which are non-proliferative and frequently exist as a minority population in recurrent therapy-resistant tumors. Progesterone receptors (PR) are known drivers of normal stem and breast CSCs. Our objective was to define novel signaling pathways governing cell fate transitions involved in driving therapy resistance in ER+ breast cancer. We reported that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, drive breast CSC outgrowth. SRC-3 knockdown abrogated PELP1-induced CSC expansion and target genes required for cell survival, suggesting an essential role for PELP1/SRC-3 complexes. PELP1 also forms a signaling and transcriptional complex with ER and PR-B. Phospho-PR species are key mediators of stemness in ER+ breast cancer models. Accordingly, PR knockdown and antiprogestins disrupted PELP1/SRC-3 complexes and blocked PELP1-induced breast CSC outgrowth. Mammary stem cell (MaSC) populations were increased in vivo in MMTV-tTA;TRE-cyto-PELP1 transgenic mice as well as in MMTV-tTA;TRE-hPR-B mice. To better understand PELP1-mediated pathways, we performed RNA-seq on MCF-7 PELP1+ models grown in tumorsphere conditions to enrich for CSC populations (ALDH+, CD44+/CD24-). Cytoplasmic PELP1-expressing cells had a different global gene profile relative to WT PELP1 (i.e. nuclear). Gene sets associated with stem cell biology, hypoxic stress, and cancer metabolism were differentially regulated, including members of the glycolytic bi-functional kinase/phosphatase PFKFB family. Seahorse metabolic phenotyping demonstrated cytoplasmic PELP1 influences metabolism by increasing both glycolysis and mitochondrial respiration. Cytoplasmic PELP1 interacted strongly with PFKFB3 and PFKFB4, and inhibition of PFKFB3 or PFKFB4 kinase activity blocked PELP1-induced tumorspheres and protein-protein interactions with SRC-3. Additionally, antiprogestin and PFKFB inhibitors were synergistic when combined with ER+ targeted therapies. These aspects of PELP1/SRC-3 biology were phenocopied in therapy resistant models (tamoxifen resistant [TamR], paclitaxel resistant [TaxR]). Together, our data suggest that PELP1, SRC-3, PR, and PFKFBs form complexes that reprogram cellular metabolism to drive breast CSC expansion. Identifying the mechanisms that regulate recurrent ER+ tumor cell populations will enable specific targeting within heterogeneous breast tumors and may lead to the development of non-ER targets that can be used in combination with endocrine treatments to overcome therapy resistance.

Molecular Mechanism and Clinical Implications of Endocrine Therapy Resistance in Breast Cancer

Oncology ◽  
2009 ◽  
Vol 77 (1) ◽  
pp. 23-37 ◽  
Author(s):  
Grazia Arpino ◽  
Carmine De Angelis ◽  
Mario Giuliano ◽  
Antonio Giordano ◽  
Claudette Falato ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Molecular Mechanism ◽  
Therapy Resistance ◽  
Clinical Implications ◽  
Endocrine Therapy Resistance

Effects of Selected Rhinologic Disorders on the Perception of Nasal Resonance in Children

1984 ◽  
Vol 15 (1) ◽  
pp. 44-50 ◽  
Author(s):  
Michael P. Rastatter ◽  
Melvin Hyman
Keyword(s):  
Allergic Rhinitis ◽  
Clinical Implications ◽  
Normal Children ◽  
Nasal Resonance

A group of sophisticated listeners judged the nasal resonance characteristics of normal children versus children evidencing selected rhinologic disorders under three speaking conditions. Results showed that perceptions of denasality are influenced by both speakers and speaking tasks. That is, children with allergic rhinitis and edemic adenoids were perceived as being denasal when they produced VCV utterances and recited sentences. However, their resonance characteristics were deemed normal for vowel productions. Interestingly, children with severely deviated septums were judged to have normal nasal resonance under all speaking conditions. Clinical implications are discussed.

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