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Advances in Cancer Metabolism and Tumour Microenvironment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 58951

Special Issue Editors

Prof. Dr. Karel Smetana, Jr.

E-Mail Website1 Website2 Website3
Guest Editor
1st Faculty Medicine, Institute of Anatomy and BIOCEV, Charles University, Prague 2 and Vestec, Prague, Czech Republic
Interests: tumor microenvironment; cutaneous malignant melanoma; cancer-associated fibroblasts; squamous epithelium; stem cells
Special Issues, Collections and Topics in MDPI journals
Dr. Michal Masarik

E-Mail Website1 Website2
Guest Editor
Department of Pathological Physiology, Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice, 562500 Brno, Czech Republic
Interests: tumor biology; biochemistry and genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

At the beginning of cancer research, attention was paid primarily to the characteristics of tumour cells themselves, however the importance of the tumour microenvironment has been revealed gradually. The simple accumulation of mutations in cancer cells was shown to be insufficient for cancer progression and for the formation of metastases. On the other hand, the key mechanisms of carcinogenesis were revealed in cell communication and metabolic interactions in the tumour microenvironment. These interactions are necessary for maintaining the energy and redox balance in cancer cells, and encompass literally all stages of tumour development. How cancer cells acquire and use different metabolites and reprogram their microenvironment to support tumour growth is an area of research that can have interesting therapeutic implications and a large impact on public health. Detecting metabolite level alterations in cancers may reveal an Achilles heel of cancer cells in the form of therapeutically-targetable metabolic dependencies. Furthermore, because of metabolite alterations, epigenetic and gene expression changes can occur through altered DNA methylation or posttranslational protein modifications. These can lead to finding new applicable cancer biomarkers. Taken together, an altered cellular metabolism is undoubtedly a key hallmark of cancer, and an understanding of cancer metabolism will probably bring novel therapeutic approaches and new hope into cancer treatment.

Prof. Karel Smetana, Jr.
Dr. Michal Masarik
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer metabolism
  • Metabolites
  • Tumour microenvironment
  • Cancer treatment
  • Tumour growth
  • DNA methylation
  • Epigenetic plasticity
  • Hallmarks of cancer

Published Papers (14 papers)

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Editorial

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4 pages, 217 KiB  
Editorial
Advances in Cancer Metabolism and Tumour Microenvironment
by Karel Smetana, Jr. and Michal Masařík
Int. J. Mol. Sci. 2022, 23(8), 4071; https://doi.org/10.3390/ijms23084071 - 7 Apr 2022
Cited by 2 | Viewed by 1592
Abstract
Cancer represents an extremely complicated ecosystem where cancer cells communicate with non-cancer cells present in the tumour niche through intercellular contacts, paracrine production of bioactive factors and extracellular vesicles, such as exosomes [...] Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)

Research

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16 pages, 3291 KiB  
Article
Altered Expression of ESR1, ESR2, PELP1 and c-SRC Genes Is Associated with Ovarian Cancer Manifestation
by Monika Englert-Golon, Mirosław Andrusiewicz, Aleksandra Żbikowska, Małgorzata Chmielewska, Stefan Sajdak and Małgorzata Kotwicka
Int. J. Mol. Sci. 2021, 22(12), 6216; https://doi.org/10.3390/ijms22126216 - 9 Jun 2021
Cited by 11 | Viewed by 3060
Abstract
Ovarian cancer remains the leading cause of death due to gynecologic malignancy. Estrogen-related pathways genes, such as estrogen receptors (ESR1 and ESR2) and their coregulators, proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), and proto-oncogene tyrosine-protein kinase c-Src (SRC) are involved in ovarian [...] Read more.
Ovarian cancer remains the leading cause of death due to gynecologic malignancy. Estrogen-related pathways genes, such as estrogen receptors (ESR1 and ESR2) and their coregulators, proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), and proto-oncogene tyrosine-protein kinase c-Src (SRC) are involved in ovarian cancer induction and development, still they require in-depth study. In our study, tissue samples were obtained from 52 females of Caucasian descent (control group without cancerous evidence (n = 27), including noncancerous benign changes (n = 15), and the ovarian carcinoma (n = 25)). Using quantitative analyses, we investigated ESRs, PELP1, and SRC mRNA expression association with ovarian tumorigenesis. Proteins’ presence and their location were determined by Western blot and immunohistochemistry. Results showed that PELP1 and SRC expression levels were found to differ in tissues of different sample types. The expression patterns were complex and differed in the case of ovarian cancer patients compared to controls. The most robust protein immunoreactivity was observed for PELP1 and the weakest for ESR1. The expression patterns of analyzed genes represent a potentially interesting target in ovarian cancer biology, especially PELP1. This study suggests that specific estrogen-mediated functions in the ovary and ovary-derived cancer might result from different local interactions of estrogen with their receptors and coregulators. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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22 pages, 5886 KiB  
Article
Radiation-Induced Senescence Reprograms Secretory and Metabolic Pathways in Colon Cancer HCT-116 Cells
by Chandrasekharam N. Nagineni, Sarwat Naz, Rajani Choudhuri, Gadisetti V. R. Chandramouli, Murali C. Krishna, Jeffrey R. Brender, John A. Cook and James B. Mitchell
Int. J. Mol. Sci. 2021, 22(9), 4835; https://doi.org/10.3390/ijms22094835 - 3 May 2021
Cited by 13 | Viewed by 3249
Abstract
Understanding the global metabolic changes during the senescence of tumor cells can have implications for developing effective anti-cancer treatment strategies. Ionizing radiation (IR) was used to induce senescence in a human colon cancer cell line HCT-116 to examine secretome and metabolome profiles. Control [...] Read more.
Understanding the global metabolic changes during the senescence of tumor cells can have implications for developing effective anti-cancer treatment strategies. Ionizing radiation (IR) was used to induce senescence in a human colon cancer cell line HCT-116 to examine secretome and metabolome profiles. Control proliferating and senescent cancer cells (SCC) exhibited distinct morphological differences and expression of senescent markers. Enhanced secretion of pro-inflammatory chemokines and IL-1, anti-inflammatory IL-27, and TGF-β1 was observed in SCC. Significantly reduced levels of VEGF-A indicated anti-angiogenic activities of SCC. Elevated levels of tissue inhibitors of matrix metalloproteinases from SCC support the maintenance of the extracellular matrix. Adenylate and guanylate energy charge levels and redox components NAD and NADP and glutathione were maintained at near optimal levels indicating the viability of SCC. Significant accumulation of pyruvate, lactate, and suppression of the TCA cycle in SCC indicated aerobic glycolysis as the predominant energy source for SCC. Levels of several key amino acids decreased significantly, suggesting augmented utilization for protein synthesis and for use as intermediates for energy metabolism in SCC. These observations may provide a better understanding of cellular senescence basic mechanisms in tumor tissues and provide opportunities to improve cancer treatment. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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13 pages, 2743 KiB  
Article
Sensitivity to Cisplatin in Head and Neck Cancer Cells Is Significantly Affected by Patient-Derived Cancer-Associated Fibroblasts
by Barbora Peltanova, Marketa Liskova, Jaromir Gumulec, Martina Raudenska, Hana Holcova Polanska, Tomas Vaculovic, David Kalfert, Marek Grega, Jan Plzak, Jan Betka and Michal Masarik
Int. J. Mol. Sci. 2021, 22(4), 1912; https://doi.org/10.3390/ijms22041912 - 15 Feb 2021
Cited by 15 | Viewed by 2640
Abstract
Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, [...] Read more.
Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different “sensitizing ratio”. Increased expression of VEGFA, PGE2S, COX2, EGFR, and NANOG in cancer cells was characteristic for the increase of resistance. On the other hand, CCL2 expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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22 pages, 5446 KiB  
Article
iPSC-Derived Hereditary Breast Cancer Model Reveals the BRCA1-Deleted Tumor Niche as a New Culprit in Disease Progression
by Lucie Portier, Christophe Desterke, Diana Chaker, Noufissa Oudrhiri, Afag Asgarova, Fatima Dkhissi, Ali G. Turhan, Annelise Bennaceur-Griscelli and Frank Griscelli
Int. J. Mol. Sci. 2021, 22(3), 1227; https://doi.org/10.3390/ijms22031227 - 27 Jan 2021
Cited by 14 | Viewed by 3925
Abstract
Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type [...] Read more.
Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a lifetime risk of developing breast and/or ovarian cancer. To model the BRCA1-deleted stroma, we first generated induced pluripotent stem cells (iPSCs) from patients carrying a germline deletion of exon 17 of the BRCA1 gene (BRCA1+/− who, based on their family histories, were at a high risk for cancer. Using peripheral blood mononuclear cells (PBMCs) of these two affected family members and two normal (BRCA1+/+) individuals, we established a number of iPSC clones via non-integrating Sendai virus-based delivery of the four OCT4, SOX2, KLF4, and c-MYC factors. Induced mesenchymal stem cells (iMSCs) were generated and used as normal and pathological stromal cells. In transcriptome analyses, BRCA1+/− iMSCs exhibited a unique pro-angiogenic signature: compared to non-mutated iMSCs, they expressed high levels of HIF-1α, angiogenic factors belonging to the VEGF, PDGF, and ANGPT subfamilies showing high angiogenic potential. This was confirmed in vitro through the increased capacity to generate tube-like structures compared to BRCA1+/+ iMSCs and in vivo by a matrigel plug angiogenesis assay where the BRCA1+/− iMSCs promoted the development of an extended and organized vessel network. We also reported a highly increased migration capacity of BRCA1+/− iMSCs through an in vitro wound healing assay that correlated with the upregulation of the periostin (POSTN). Finally, we assessed the ability of both iMSCs to facilitate the engraftment of murine breast cancer cells using a xenogenic 4T1 transplant model. The co-injection of BRCA1+/− iMSCs and 4T1 breast cancer cells into mouse mammary fat pads gave rise to highly aggressive tumor growth (2-fold increase in tumor volume compared to 4T1 alone, p = 0.01283) and a higher prevalence of spontaneous metastatic spread to the lungs. Here, we report for the first time a major effect of BRCA1 haploinsufficiency on tumor-associated stroma in the context of BRCA1-associated cancers. The unique iMSC model used here was generated using patient-specific iPSCs, which opens new therapeutic avenues for the prevention and personalized treatment of BRCA1-associated hereditary breast cancer. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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20 pages, 2342 KiB  
Article
Regulation of Fibroblast Activation Protein by Transforming Growth Factor Beta-1 in Glioblastoma Microenvironment
by Evzen Krepela, Zdislava Vanickova, Petr Hrabal, Michal Zubal, Barbora Chmielova, Eva Balaziova, Petr Vymola, Ivana Matrasova, Petr Busek and Aleksi Sedo
Int. J. Mol. Sci. 2021, 22(3), 1046; https://doi.org/10.3390/ijms22031046 - 21 Jan 2021
Cited by 16 | Viewed by 4115
Abstract
The proline-specific serine protease fibroblast activation protein (FAP) can participate in the progression of malignant tumors and represents a potential diagnostic and therapeutic target. Recently, we demonstrated an increased expression of FAP in glioblastomas, particularly those of the mesenchymal subtype. Factors controlling FAP [...] Read more.
The proline-specific serine protease fibroblast activation protein (FAP) can participate in the progression of malignant tumors and represents a potential diagnostic and therapeutic target. Recently, we demonstrated an increased expression of FAP in glioblastomas, particularly those of the mesenchymal subtype. Factors controlling FAP expression in glioblastomas are unknown, but evidence suggests that transforming growth factor beta (TGFbeta) can trigger mesenchymal changes in these tumors. Here, we investigated whether TGFbeta promotes FAP expression in transformed and stromal cells constituting the glioblastoma microenvironment. We found that both FAP and TGFbeta-1 are upregulated in glioblastomas and display a significant positive correlation. We detected TGFbeta-1 immunopositivity broadly in glioblastoma tissues, including tumor parenchyma regions in the immediate vicinity of FAP-immunopositive perivascular stromal cells. Wedemonstrate for the first time that TGFbeta-1 induces expression of FAP in non-stem glioma cells, pericytes, and glioblastoma-derived endothelial and FAP+ mesenchymal cells, but not in glioma stem-like cells. In glioma cells, this effect is mediated by the TGFbeta type I receptor and canonical Smad signaling and involves activation of FAP gene transcription. We further present evidence of FAP regulation by TGFbeta-1 secreted by glioma cells. Our results provide insight into the previously unrecognized regulation of FAP expression by autocrine and paracrine TGFbeta-1 signaling in a broad spectrum of cell types present in the glioblastoma microenvironment. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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Review

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18 pages, 2479 KiB  
Review
Harnessing Metabolic Reprogramming to Improve Cancer Immunotherapy
by Liang Yan, Yanlian Tan, Guo Chen, Jun Fan and Jun Zhang
Int. J. Mol. Sci. 2021, 22(19), 10268; https://doi.org/10.3390/ijms221910268 - 24 Sep 2021
Cited by 13 | Viewed by 3870
Abstract
Immune escape is one of the hallmarks of cancer. While metabolic reprogramming provides survival advantage to tumor cancer cells, accumulating data also suggest such metabolic rewiring directly affects the activation, differentiation and function of immune cells, particularly in the tumor microenvironment. Understanding how [...] Read more.
Immune escape is one of the hallmarks of cancer. While metabolic reprogramming provides survival advantage to tumor cancer cells, accumulating data also suggest such metabolic rewiring directly affects the activation, differentiation and function of immune cells, particularly in the tumor microenvironment. Understanding how metabolic reprogramming affects both tumor and immune cells, as well as their interplay, is therefore critical to better modulate tumor immune microenvironment in the era of cancer immunotherapy. In this review, we discuss alterations in several essential metabolic pathways in both tumor and key immune cells, provide evidence on their dynamic interaction, and propose innovative strategies to improve cancer immunotherapy via the modulation of metabolic pathways. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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35 pages, 2975 KiB  
Review
Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy
by Miljana Nenkov, Yunxia Ma, Nikolaus Gaßler and Yuan Chen
Int. J. Mol. Sci. 2021, 22(12), 6262; https://doi.org/10.3390/ijms22126262 - 10 Jun 2021
Cited by 52 | Viewed by 7972
Abstract
Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that [...] Read more.
Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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15 pages, 9457 KiB  
Review
Breast Cancer: Targeting of Steroid Hormones in Cancerogenesis and Diagnostics
by Marcela Valko-Rokytovská, Peter Očenáš, Aneta Salayová and Zuzana Kostecká
Int. J. Mol. Sci. 2021, 22(11), 5878; https://doi.org/10.3390/ijms22115878 - 30 May 2021
Cited by 21 | Viewed by 4499
Abstract
Breast cancer is the most common malignancy in women with high mortality. Sensitive and specific methods for the detection, characterization and quantification of endogenous steroids in body fluids or tissues are needed for the diagnosis, treatment and prognosis of breast cancer and many [...] Read more.
Breast cancer is the most common malignancy in women with high mortality. Sensitive and specific methods for the detection, characterization and quantification of endogenous steroids in body fluids or tissues are needed for the diagnosis, treatment and prognosis of breast cancer and many other diseases. At present, non-invasive diagnostic methods are gaining more and more prominence, which enable a relatively fast and painless way of detecting many diseases. Metabolomics is a promising analytical method, the principle of which is the study and analysis of metabolites in biological material. It represents a comprehensive non-invasive diagnosis, which has a high potential for use in the diagnosis and prognosis of cancers, including breast cancer. This short review focuses on the targeted metabolomics of steroid hormones, which play an important role in the development and classification of breast cancer. The most commonly used diagnostic tool is the chromatographic method with mass spectrometry detection, which can simultaneously determine several steroid hormones and metabolites in one sample. This analytical procedure has a high potential in effective diagnosis of steroidogenesis disorders. Due to the association between steroidogenesis and breast cancer progression, steroid profiling is an important tool, as well as in monitoring disease progression, improving prognosis, and minimizing recurrence. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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21 pages, 1361 KiB  
Review
Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer
by Renata Novak Kujundžić, Marin Prpić, Nikola Đaković, Nina Dabelić, Marko Tomljanović, Anamarija Mojzeš, Ana Fröbe and Koraljka Gall Trošelj
Int. J. Mol. Sci. 2021, 22(11), 5681; https://doi.org/10.3390/ijms22115681 - 26 May 2021
Cited by 14 | Viewed by 4870
Abstract
The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and [...] Read more.
The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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23 pages, 3623 KiB  
Review
From Metabolism to Genetics and Vice Versa: The Rising Role of Oncometabolites in Cancer Development and Therapy
by Emanuela Di Gregorio, Gianmaria Miolo, Asia Saorin, Agostino Steffan and Giuseppe Corona
Int. J. Mol. Sci. 2021, 22(11), 5574; https://doi.org/10.3390/ijms22115574 - 25 May 2021
Cited by 7 | Viewed by 3623
Abstract
Over the last decades, the study of cancer metabolism has returned to the forefront of cancer research and challenged the role of genetics in the understanding of cancer development. One of the major impulses of this new trend came from the discovery of [...] Read more.
Over the last decades, the study of cancer metabolism has returned to the forefront of cancer research and challenged the role of genetics in the understanding of cancer development. One of the major impulses of this new trend came from the discovery of oncometabolites, metabolic intermediates whose abnormal cellular accumulation triggers oncogenic signalling and tumorigenesis. These findings have led to reconsideration and support for the long-forgotten hypothesis of Warburg of altered metabolism as oncogenic driver of cancer and started a novel paradigm whereby mitochondrial metabolites play a pivotal role in malignant transformation. In this review, we describe the evolution of the cancer metabolism research from a historical perspective up to the oncometabolites discovery that spawned the new vision of cancer as a metabolic disease. The oncometabolites’ mechanisms of cellular transformation and their contribution to the development of new targeted cancer therapies together with their drawbacks are further reviewed and discussed. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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Graphical abstract

16 pages, 787 KiB  
Review
KRAS, A Prime Mediator in Pancreatic Lipid Synthesis through Extra Mitochondrial Glutamine and Citrate Metabolism
by Isaac James Muyinda, Jae-Gwang Park, Eun-Jung Jang and Byong-Chul Yoo
Int. J. Mol. Sci. 2021, 22(10), 5070; https://doi.org/10.3390/ijms22105070 - 11 May 2021
Cited by 7 | Viewed by 3281
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven pancreatic cancer is very lethal, with a five-year survival rate of <9%, irrespective of therapeutic advances. Different treatment modalities including chemotherapy, radiotherapy, and immunotherapy demonstrated only marginal efficacies because of pancreatic tumor specificities. Surgery at the [...] Read more.
Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven pancreatic cancer is very lethal, with a five-year survival rate of <9%, irrespective of therapeutic advances. Different treatment modalities including chemotherapy, radiotherapy, and immunotherapy demonstrated only marginal efficacies because of pancreatic tumor specificities. Surgery at the early stage of the disease remains the only curative option, although only in 20% of patients with early stage disease. Clinical trials targeting the main oncogenic driver, KRAS, have largely been unsuccessful. Recently, global metabolic reprogramming has been identified in patients with pancreatic cancer and oncogenic KRAS mouse models. The newly reprogrammed metabolic pathways and oncometabolites affect the tumorigenic environment. The development of methods modulating metabolic reprogramming in pancreatic cancer cells might constitute a new approach to its therapy. In this review, we describe the major metabolic pathways providing acetyl-CoA and NADPH essential to sustain lipid synthesis and cell proliferation in pancreatic cancer cells. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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12 pages, 1189 KiB  
Review
Molecular Characteristics of Amyloid Precursor Protein (APP) and Its Effects in Cancer
by Han Na Lee, Mi Suk Jeong and Se Bok Jang
Int. J. Mol. Sci. 2021, 22(9), 4999; https://doi.org/10.3390/ijms22094999 - 8 May 2021
Cited by 25 | Viewed by 4681
Abstract
Amyloid precursor protein (APP) is a type 1 transmembrane glycoprotein, and its homologs amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) are highly conserved in mammals. APP and APLP are known to be intimately involved in the pathogenesis and progression [...] Read more.
Amyloid precursor protein (APP) is a type 1 transmembrane glycoprotein, and its homologs amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) are highly conserved in mammals. APP and APLP are known to be intimately involved in the pathogenesis and progression of Alzheimer’s disease and to play important roles in neuronal homeostasis and development and neural transmission. APP and APLP are also expressed in non-neuronal tissues and are overexpressed in cancer cells. Furthermore, research indicates they are involved in several cancers. In this review, we examine the biological characteristics of APP-related family members and their roles in cancer. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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20 pages, 1473 KiB  
Review
The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence
by Assunta Virtuoso, Roberto Giovannoni, Ciro De Luca, Francesca Gargano, Michele Cerasuolo, Nicola Maggio, Marialuisa Lavitrano and Michele Papa
Int. J. Mol. Sci. 2021, 22(7), 3301; https://doi.org/10.3390/ijms22073301 - 24 Mar 2021
Cited by 32 | Viewed by 5245
Abstract
Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. [...] Read more.
Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies. Full article
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)
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