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Dear Colleagues, Malignant tumors develop distant metastases, e.g., small clusters of cells that detach from the primitive site and colonize distant organs and tissues. Unlike the primary masses, metastases are often difficult to fully eradicate by surgery ablation and are almost always the primary object of chemo- and/or immune-therapies. The presence of metastases at tumor diagnosis is responsible for the unfavorable prognosis and of relapses even after initially successful tumor therapies. The lack of success of chemo- and immune-therapy approaches depends on many factors among which, the inadequate capacity of the anti-tumor drugs of reaching appropriate concentrations in the organs and tissues involved in the metastatic growth is a major concern. Another factor is the complexity of the metastasis biology and of their molecular behavior, evidencing a population of tumor cells with a genetic compartment different from that of the tumor of origin. The involvement of host cells and factors recruited by the metastatic cells and committed to support the metastatic growth is also an event crucial for the lack of success of the anti-tumor therapy. The knowledge of the molecular biology of metastases is mandatory to support the search for chemical agents to treat the metastatic determinants and to control of the neoplastic disease. This Special Issue on “Chemical and Molecular Approach to Tumor Metastases” will explore the impact of biology, molecular medicine and chemistry on all aspects related to tumor metastases from the biological and molecular aspects of the metastatic growth, including the relationships between the metastatic cells and the host environment, and the search for druggable determinants useful for the chemical analysis of agents selectively active against tumor metastases. With the combination of invited reviews and original papers from prominent scientists working on all aspects of molecular medicine and cancer therapy, such as, but not limited to: drug delivery, genomics, chemoprevention, drug discovery, we aim to sample recent progress in molecular and chemical aspects of therapy of malignant tumors. Clinical success studies and evidences of novel compounds are particularly welcome.

tumor metastasis --- biology of metastasis --- genomics of metastasis --- epigenetics of metastasis --- dynamics of metastasis --- metastasis niche --- microenvironment --- immunotherapy --- chemotherapy --- molecular approaches --- chemical approaches --- metastasis druggable targets --- innovative drugs --- clinical studies

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Development of an effective anticancer therapeutic necessitates the selection of cancer-related or cancer-specific pathways or molecules that are sensitive to intervention. Several such critical yet sensitive molecular targets have been recognized, and their specific antagonists or inhibitors validated as potential therapeutics in preclinical models. Yet, majority of anticancer principles or therapeutics show limited success in the clinical translation. Thus, the need for the development of an effective therapeutic strategy persists. “Altered energy metabolism” in cancer is one of the earliest known biochemical phenotypes which dates back to the early 20th century. The German scientist, Otto Warburg and his team (Warburg, Wind, Negelein 1926; Warburg, Wind, Negelein 1927) provided the first evidence that the glucose metabolism of cancer cells diverge from normal cells. This phenomenal discovery on deregulated glucose metabolism or cellular bioenergetics is frequently witnessed in majority of solid malignancies. Currently, the altered glucose metabolism is used in the clinical diagnosis of cancer through positron emission tomography (PET) imaging. Thus, the “deregulated bioenergetics” is a clinically relevant metabolic signature of cancer cells, hence recognized as one of the hallmarks of cancer (Hanahan and Weinberg 2011). Accumulating data unequivocally demonstrate that, besides cellular bioenergetics, cancer metabolism facilitates several cancer-related processes including metastasis, therapeutic resistance and so on. Recent reports also demonstrate the oncogenic regulation of glucose metabolism (e.g. glycolysis) indicating a functional link between neoplastic growth and cancer metabolism. Thus, cancer metabolism, which is already exploited in cancer diagnosis, remains an attractive target for therapeutic intervention as well. The Frontiers in Oncology Research Topic “Cancer Metabolism: Molecular Targeting and Implications for Therapy” emphases on recent advances in our understanding of metabolic reprogramming in cancer, and the recognition of key molecules for therapeutic targeting. Besides, the topic also deliberates the implications of metabolic targeting beyond the energy metabolism of cancer. The research topic integrates a series of reviews, mini-reviews and original research articles to share current perspectives on cancer metabolism, and to stimulate an open forum to discuss potential challenges and future directions of research necessary to develop effective anticancer strategies.

Cancer Metabolism --- Tumor microenvironment --- metabolic reprogramming --- Warburg effect --- metastasis --- glycolysis --- immunotherapy --- epigenetic regulation

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Calcium is vital for human physiology; it mediates multiple signaling cascades, critical for cell survival, differentiation, or death both as first and as second messenger. The role of calcium as first messenger is mediated by the G-protein coupled receptor, the extracellular calcium-sensing receptor (CaSR). The CaSR is a multifaceted molecule that senses changes in the concentration of a wide variety of environmental factors including di- and trivalent cations, amino acids, polyamines, and pH. In calcitropic tissues with obvious roles in calcium homeostasis such as parathyroid, kidney, and bone it regulates circulating calcium concentrations. The germline mutations of the CaSR cause parathyroid disorders demonstrating the importance of the CaSR for the maintenance of serum calcium homeostasis. The CaSR has an important role also in a range of non-calcitropic tissues, such as the intestine, lungs, central and peripheral nervous system, breast, skin and reproductive system, where it regulates molecular and cellular processes such as gene expression, proliferation, differentiation and apoptosis; as well as regulating hormone secretion and lactation.This Research Topic is an overview of the CaSR and its molecular signaling properties together with the various organ systems where it plays an important role. The articles highlight the current knowledge regarding many aspects of the calcitropic and non-calcitropic physiology and pathophysiology of the CaSR.

G protein-coupled receptor (GPCR) --- crystal structure --- parathyroid hormone (PTH) --- vitamin D --- proliferation and differentiation --- metastasis --- cancer --- Alzheimer

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The epithelial-to-mesenchymal transition (EMT) is a highly dynamic process with multiple transitional states, by which epithelial cells can convert into a mesenchymal phenotype. This process involves loss of cellular adhesion and cellular polarity, and an improvement in migratory and invasive properties. It occurs during normal embryonic development, tissue regeneration, organ fibrosis, and wound healing. It is also involved in tumor progression with metastatic expansion, and plays a major role in resistance to cancer treatment. In cancers, EMT inducers are hypoxia, cytokines and growth factors secreted by the tumor microenvironment, stroma crosstalk, metabolic changes, innate and adaptive immune responses, and treatment with antitumor drugs. Switch in gene expression from epithelial to mesenchymal phenotype is triggered by complex regulatory networks involving transcriptional control, non-coding RNAs, chromatin remodeling and epigenetic modifications, alternative splicing, post-translational regulation, protein stability and subcellular localization. Reversion of EMT, the mesenchymal-to-epithelial transition (MET), affects circulating cancer cells when they reach a desirable metastatic niche to develop secondary tumors. More knowledge and control of EMT to MET is necessary and will be beneficial for patients for cancer treatment. This current Special Issue entitled “Epithelial to Mesenchymal Transition in Cancer” will address these questions.

Epithelial-to-mesenchymal transition (EMT) --- cancer --- metastasis --- chemoresistance --- cancer therapy, epigenetics --- non-coding RNAs --- TGF-beta --- PLK1 --- CK2, exosomes --- epithelial-to-pericyte transition (EPT)

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Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in all kingdoms of life, as they equilibrate the reaction between three simple but essential chemical species: CO2, bicarbonate, and protons. Discovered more than 80 years ago, in 1933, these enzymes have been extensively investigated due to the biomedical application of their inhibitors, but also because they are an extraordinary example of convergent evolution, with seven genetically distinct CA families that evolved independently in Bacteria, Archaea, and Eukarya. CAs are also among the most efficient enzymes known in nature, due to the fact that the uncatalyzed hydration of CO2 is a very slow process and the physiological demands for its conversion to ionic, soluble species is very high. Inhibition of the CAs has pharmacological applications in many fields, such as antiglaucoma, anticonvulsant, antiobesity, and anticancer agents/diagnostic tools, but is also emerging for designing anti-infectives, i.e., antifungal, antibacterial, and antiprotozoan agents with a novel mechanism of action. Mitochondrial CAs are implicated in de novo lipogenesis, and thus selective inhibitors of such enzymes may be useful for the development of new antiobesity drugs. As tumor metabolism is diverse compared to that of normal cells, ultimately, relevant contributions on the role of the tumor-associated isoforms CA IX and XII in these phenomena have been published and the two isoforms have been validated as novel antitumor/antimetastatic drug targets, with antibodies and small-molecule inhibitors in various stages of clinical development. CAs also play a crucial role in other metabolic processes connected with urea biosynthesis, gluconeogenesis, and so on, since many carboxylation reactions catalyzed by acetyl-coenzyme A carboxylase or pyruvate carboxylase use bicarbonate, not CO2, as a substrate. In organisms other than mammals, e.g., plants, algae, and cyanobacteria, CAs are involved in photosynthesis, whereas in many parasites (fungi, protozoa), they are involved in the de novo synthesis of important metabolites (lipids, nucleic acids, etc.). The metabolic effects related to interference with CA activity, however, have been scarcely investigated. The present Special Issue of Metabolites aims to fill this gap by presenting the latest developments in the field of CAs and their role in metabolism.

tumor --- metabolism --- carbonic anhydrase --- isoforms IX and XII --- inhibitor --- sulfonamide --- antibody --- bacterial carbonic anhydrases --- inhibitors --- antibiotic --- CO2 capture --- engineered bacteria --- acidity --- hypoxia --- pH --- carbonic anhydrases --- V-ATPases --- proton pump inhibitors --- carbonic anhydrase inhibitors --- carbonic anhydrase IX --- cancer --- hypoxia --- radiation --- resistance --- tumors --- pH --- carbonic anhydrases --- metalloenzymes --- carbonic anhydrase IX --- carbonic anhydrase XII --- cancer therapeutics --- metabolism --- tumor microenvironment --- drug discovery --- hypoxia --- carbonic anhydrase IX --- cancer metabolism --- transporter --- integrin --- MMP14 --- migration --- invasion --- metastasis --- carbonic anhydrases --- CA gene family --- Chlamydomonas reinhardtii --- model alga --- metabolic role --- photosynthesis --- carbonic anhydrase --- hypoxic tumor --- metabolism --- carboxylation --- bicarbonate --- pH regulation --- antitumor agent --- sulfonamide --- bacterial enzymes --- carbonic anhydrase --- enzyme inhibition --- metalloenzymes --- amino acid --- glaucoma --- tumors --- carbonic anhydrase --- human isoform --- sulfonamide --- benzamide --- pathogens --- Entamoeba histolytica --- carbonic anhydrase --- metalloenzymes --- protozoan --- amine --- amino acid --- activator