scholarly journals Metabolic reprogramming and cancer progression

Science ◽  
2020 ◽  
Vol 368 (6487) ◽  
pp. eaaw5473 ◽  
Author(s):  
Brandon Faubert ◽  
Ashley Solmonson ◽  
Ralph J. DeBerardinis
Keyword(s):  
Recent Work ◽  
Experimental Model ◽  
Cancer Progression ◽  
Metastatic Cancer ◽  
Tumor Biology ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Primary Tumors ◽  
Metabolic Properties ◽  
Metabolic Heterogeneity

Metabolic reprogramming is a hallmark of malignancy. As our understanding of the complexity of tumor biology increases, so does our appreciation of the complexity of tumor metabolism. Metabolic heterogeneity among human tumors poses a challenge to developing therapies that exploit metabolic vulnerabilities. Recent work also demonstrates that the metabolic properties and preferences of a tumor change during cancer progression. This produces distinct sets of vulnerabilities between primary tumors and metastatic cancer, even in the same patient or experimental model. We review emerging concepts about metabolic reprogramming in cancer, with particular attention on why metabolic properties evolve during cancer progression and how this information might be used to develop better therapeutic strategies.

scholarly journals TAMI-06. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Jenna Minami ◽  
Nicholas Bayley ◽  
Christopher Tse ◽  
Henan Zhu ◽  
Danielle Morrow ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cultured Cells ◽  
Tumor Biology ◽  
Metabolic Reprogramming ◽  
Neoplastic Progression ◽  
Extracellular Milieu ◽  
Metabolic Defects ◽  
Metabolic Heterogeneity

Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.

scholarly journals Cancer-Associated Cachexia: A Systemic Consequence of Cancer Progression

2020 ◽  
Vol 4 (1) ◽  
pp. 391-411
Author(s):  
Anup K. Biswas ◽  
Swarnali Acharyya
Keyword(s):  
Cancer Patients ◽  
Cancer Progression ◽  
Metastatic Cancer ◽  
Therapeutic Strategies ◽  
Invasive Growth ◽  
Wasting Syndrome ◽  
Life Threatening ◽  
And Function ◽  
Related Mortality

Cancer is a life-threatening disease that has plagued humans for centuries. The vast majority of cancer-related mortality results from metastasis. Indeed, the invasive growth of metastatic cancer cells in vital organs causes fatal organ dysfunction, but metastasis-related deaths also result from cachexia, a debilitating wasting syndrome characterized by an involuntary loss of skeletal muscle mass and function. In fact, about 80% of metastatic cancer patients suffer from cachexia, which often renders them too weak to tolerate standard doses of anticancer therapies and makes them susceptible to death from cardiac and respiratory failure. The goals of this review are to highlight important findings that help explain how cancer-induced systemic changes drive the development of cachexia and to discuss unmet challenges and potential therapeutic strategies targeting cachexia to improve the quality of life and survival of cancer patients.

scholarly journals Metastasis-associated fibroblasts: an emerging target for metastatic cancer

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Zimu Wang ◽  
Jiaxin Liu ◽  
Hairong Huang ◽  
Mingxiang Ye ◽  
Xinying Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Metastatic Cancer ◽  
Antiangiogenic Therapy ◽  
Treatment Strategies ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Metastatic Tumors ◽  
Stromal Fibroblasts ◽  
Primary Tumors ◽  
Metastatic Sites

AbstractMetastasis suggests a poor prognosis for cancer patients, and treatment strategies for metastatic cancer are still very limited. Numerous studies have shown that cancer-associated fibroblasts (CAFs), a large component of the tumor microenvironment, contribute to tumor metastasis. Stromal fibroblasts at metastatic sites are different from CAFs within primary tumors and can be termed metastasis-associated fibroblasts (MAFs), and they also make great contributions to the establishment of metastatic lesions and the therapeutic resistance of metastatic tumors. MAFs are capable of remodeling the extracellular matrix of metastatic tumors, modulating immune cells in the tumor microenvironment, promoting angiogenesis and enhancing malignant tumor phenotypes. Thus, MAFs can help establish premetastatic niches and mediate resistance to therapeutic strategies, including immunotherapy and antiangiogenic therapy. The results of preclinical studies suggest that targeting MAFs can alleviate the progression of metastatic cancer and mitigate therapeutic resistance, indicating that MAFs are a promising target for metastatic cancer. Here, we comprehensively summarize the existing evidence on MAFs and discuss their origins, generation, functions and related therapeutic strategies in an effort to provide a better understanding of MAFs and offer treatment perspectives for metastatic cancer.

scholarly journals The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance

2019 ◽  
Vol 20 (14) ◽  
pp. 3602 ◽  
Author(s):  
Magdalena Rudzińska ◽  
Alessandro Parodi ◽  
Surinder M. Soond ◽  
Andrey Z. Vinarov ◽  
Dmitry O. Korolev ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Lysosomal Enzymes ◽  
Tumor Biology ◽  
Therapeutic Strategies ◽  
Cysteine Cathepsins ◽  
Aggressive Tumor ◽  
Tumor Phenotypes

Cysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology.

scholarly journals The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

2022 ◽  
Author(s):  
Anna Sebestyén ◽  
Titanilla Dankó ◽  
Dániel Sztankovics ◽  
Dorottya Moldvai ◽  
Regina Raffay ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Metabolic Phenotyping ◽  
Regulatory Pathways ◽  
Metabolic Plasticity ◽  
Cancer Management ◽  
Mtor Kinase

AbstractDespite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.

Evaluating PSA nadir drift in high-risk and metastatic prostate cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 310-310
Author(s):  
Eric Tyler Miller ◽  
Lorna Kwan ◽  
Sandy Liu ◽  
Isla Garraway
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Distant Metastases ◽  
Tumor Resistance ◽  
Current Standard ◽  
Primary Tumors ◽  
Gleason Pattern ◽  
Psa Nadir

310 Background: Prostate cancer (PC) is a heterogeneous, clinically disparate, and often unpredictable disease whereby nearly 3% of patients present with bone metastatic PC (BMPC). Virtually all patients diagnosed with stage M1 disease fail to achieve complete remission and rapidly progress to castration-resistant PC (CRPC) and death (28% 5-year survival). Androgen deprivation therapy (ADT), the current standard of care for M1 disease, does not induce durable remissions. Improved understanding of tumor biology associated with lethal progression is desperately needed to guide clinical trials. Methods: We assembled a diverse, clinically annotated biorepository with diagnostic biopsy tissue from 428 patients with high-risk M0 and M1 disease. Retrospective analysis was performed on M0 (n = 157) and M1 (n = 112) patients stratified by treatment sequence. Clinical and pathological variables analyzed included age at diagnosis, race, primary Gleason sum, tumor burden, initial treatment received, PSA at time of biopsy, PSA velocity and length of follow-up. Primary endpoints included PSA nadir per treatment round, time from biopsy to CRPC, and death. Results: Compared to M0 cases, M1 patients were older, displayed significantly higher PSAs at the time of biopsy, and were more likely to display primary Gleason pattern 5. Patients with stage M1 disease had significantly worse survival, shorter time to CRPC, and median PSA nadir following each treatment round never fell below 2ng/ml. Median PSA nadirs associated with each treatment round demonstrated marked upward drift in the M1 cohort when compared to the M0 cohort. Conclusions: The presence of distant metastases is a major obstacle in achieving durable remissions for very high-risk PC. Our data confirms that ADT has limited effect on controlling cancer progression in M1 patients. PSA nadir drift in M1 compared to M0 patients may indicate intrinsic tumor resistance to currently available therapies. Multimodal profiling of M1 primary tumors may reveal actionable targets for initiation of combination treatment regimens at diagnosis.

scholarly journals ETMM-02. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i14-i14
Author(s):  
Jenna Minami ◽  
Nicholas Bayley ◽  
Christopher Tse ◽  
Henan Zhu ◽  
Danielle Morrow ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cultured Cells ◽  
Tumor Biology ◽  
Metabolic Reprogramming ◽  
Neoplastic Progression ◽  
Extrinsic Factors ◽  
Extracellular Milieu ◽  
Metabolic Heterogeneity

Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations in response to a multitude of intrinsic and extrinsic factors to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.

scholarly journals Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 135 ◽  
Author(s):  
Rosario Avolio ◽  
Danilo Swann Matassa ◽  
Daniela Criscuolo ◽  
Matteo Landriscina ◽  
Franca Esposito
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Tumor Necrosis Factor Receptor ◽  
Heat Shock Protein 90 ◽  
Response To Therapy ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
And Oxidative Stress

Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s.

Targeting Tumour Metastasis: The Emerging Role of Nanotechnology

2020 ◽  
Vol 27 (8) ◽  
pp. 1367-1381 ◽  
Author(s):  
Sarah Visentin ◽  
Mirela Sedić ◽  
Sandra Kraljević Pavelić ◽  
Krešimir Pavelić
Keyword(s):  
Cancer Progression ◽  
Metastatic Cancer ◽  
Treatment Strategies ◽  
Metastatic Progression ◽  
Therapeutic Concept ◽  
Molecular Alterations ◽  
Tumour Metastasis ◽  
Metastatic Cells ◽  
Metastatic Process ◽  
Underlying Mechanisms

The metastatic process has still not been completely elucidated, probably due to insufficient knowledge of the underlying mechanisms. Here, we provide an overview of the current findings that shed light on specific molecular alterations associated with metastasis and present novel concepts in the treatment of the metastatic process. In particular, we discuss novel pharmacological approaches in the clinical setting that target metastatic progression. New insights into the process of metastasis allow optimisation and design of new treatment strategies, especially in view of the fact that metastatic cells share common features with stem cells. Nano- and micro-technologies are herein elaborated in details as a promising therapeutic concept in targeted drug delivery for metastatic cancer. Progression in the field could provide a more efficient way to tackle metastasis and thus bring about advancements in the treatment and management of patients with advanced cancer.

scholarly journals Shared and unique metabolic features of the malignant and benign thyroid lesions determined with use of 1H HR MAS NMR spectroscopy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Agnieszka Skorupa ◽  
Mateusz Ciszek ◽  
Ewa Chmielik ◽  
Łukasz Boguszewicz ◽  
Małgorzata Oczko-Wojciechowska ◽  
...  
Keyword(s):  
Nmr Spectra ◽  
Univariate Analysis ◽  
Mas Nmr ◽  
Metabolic Reprogramming ◽  
Benign Lesions ◽  
Chronic Thyroiditis ◽  
Malignant Lesions ◽  
Metabolic Heterogeneity ◽  
Benign Thyroid ◽  
Thyroid Lesions

AbstractThe purpose of this work was to investigate the distinct and common metabolic features of the malignant and benign thyroid lesions in reference to the non-transformed tissue from the contralateral gland (chronic thyroiditis and colloid goiter). 1H HR MAS NMR spectra of 38 malignant lesions, 32 benign lesions and 112 samples from the non-tumoral tissue (32 from chronic thyroiditis and 80 samples from colloid goiter) were subjected both to multivariate and univariate analysis. The increased succinate, glutamine, glutathione, serine/cysteine, ascorbate, lactate, taurine, threonine, glycine, phosphocholine/glycerophosphocholine and decreased lipids were found in both lesion types in comparison to either colloid goiter or chronic thyroiditis. The elevated glutamate and choline, and reduced citrate and glucose were additionally evident in these lesions in reference to goiter, while the increased myo-inositol—in comparison to thyroiditis. The malignant lesions were characterized by the higher alanine and lysine levels than colloid goiter and thyroiditis, while scyllo-inositol was uniquely increased in the benign lesions (not in cancer) in comparison to both non-tumoral tissue types. Moreover, the benign lesions presented with the unique increase of choline in reference to thyroiditis (not observed in the cancerous tissue). The metabolic heterogeneity of the non-tumoral tissue should be considered in the analysis of metabolic reprogramming in the thyroid lesions.

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