Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine.

In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.

Cysteine metabolic circuitries: druggable targets in cancer.

To enable survival in adverse conditions, cancer cells undergo global metabolic adaptations. The amino acid cysteine actively contributes to cancer metabolic remodelling on three different levels: first, in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, a reversible post-translational modification; second, as a substrate for the production of hydrogen sulphide (H2S), which feeds the mitochondrial electron transfer chain and mediates per-sulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, finally, as a carbon source for epigenetic regulation, biomass production and energy production. This review will provide a systematic portrayal of the role of cysteine in cancer biology as a source of carbon and sulphur atoms, the pivotal role of cysteine in different metabolic pathways and the importance of H2S as an energetic substrate and signalling molecule. The different pools of cysteine in the cell and within the body, and their putative use as prognostic cancer markers will be also addressed. Finally, we will discuss the pharmacological means and potential of targeting cysteine metabolism for the treatment of cancer.

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives.

Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.

Metabolic Remodeling as a Way of Adapting to Tumor Microenvironment (TME), a Job of Several Holders.

The microenvironment depends and generates dependence on all the cells and structures that share the same niche, the biotope. The contemporaneous view of the tumor microenvironment (TME) agrees with this idea. The cells that make up the tumor, whether malignant or not, behave similarly to classes of elements within a living community. These elements inhabit, modify and benefit from all the facilities the microenvironment has to offer and that will contribute to the survival and growth of the tumor and the progression of the disease.The metabolic adaptation to microenvironment is a crucial process conducting to an established tumor able to grow locally, invade and metastasized. The metastatic cancer cells are reasonable more plastic than non-metastatic cancer cells, because the previous ones must survive in the microenvironment where the primary tumor develops and in addition, they must prosper in the microenvironment in the metastasized organ.The metabolic remodeling requires not only the adjustment of metabolic pathways per se but also the readjustment of signaling pathways that will receive and obey to the extracellular instructions, commanding the metabolic adaptation. Many diverse players are pivotal in cancer metabolic fitness from the initial signaling stimuli, going through the activation or repression of genes, until the phenotype display. The new phenotype will permit the import and consumption of organic compounds, useful for energy and biomass production, and the export of metabolic products that are useless or must be secreted for a further recycling or controlled uptake. In the metabolic network, three subsets of players are pivotal: (1) the organic compounds; (2) the transmembrane transporters, and (3) the enzymes.This chapter will present the "Pharaonic" intent of diagraming the interplay between these three elements in an attempt of simplifying and, at the same time, of showing the complex sight of cancer metabolism, addressing the orchestrating role of microenvironment and highlighting the influence of non-cancerous cells.

Recycling the Interspecific Relations with Epithelial Cells: Bacteria and Cancer Metabolic Symbiosis.

Several aspects of the human physiology are controlled by the microbiota that plays a key role in health and disease. In fact, microbial dysbiosis is associated with numerous diseases, including several types of cancer such as colon, gastric, esophageal, pancreatic, laryngeal, breast and gallbladder carcinomas.Metabolic symbiosis between non-malignant cells and the resident microbita is crucial for the host homeostasis. However, cancer cells are able to repurpose the pre-existing metabolic symbiosis, being able to recycle those relations and also create novel metabolic symbiosis, leading to profound alterations on the local microenvironment.In here we will explore some of these symbiotic metabolic interactions between bacteria and non-malignant cells in two different contexts: colon and uterine cervix. The way malignant cells are able to recycle these normal interactions and also create novel types of symbiotic metabolic relations will also be discussed.The knowledge of these complex interactions and recycling mechanisms is of extreme importance for cancer treatment, as new therapeutic targets could be developed.

Endothelial Cells (ECs) Metabolism: A Valuable Piece to Disentangle Cancer Biology.

Effective therapies to fight cancer should not be focused specifically on cancer cells, but it should consider the various components of the TME. Non-cancerous cells cooperate with cancer cells by sharing signaling and organic molecules, accounting for cancer progression. Most of the anti-angiogenic therapy clinically approved for the treatment of human diseases relies on targeting vascular endothelial growth factor (VEGF) signaling pathway. Unexpectedly and unfortunately, the results of anti-angiogenic therapies in the treatment of human diseases are not so effective, showing an insufficient efficacy and resistance.This chapter will give some insights on showing that targeting endothelial cell metabolism is a missing piece to revolutionize cancer therapy. Only recently endothelial cell (EC) metabolism has been granted as an important inducer of angiogenesis. Metabolic studies in EC demonstrated that targeting EC metabolism can be an alternative to overcome the failure of anti-angiogenic therapies. Hence, it is urgent to increase the knowledge on how ECs alter their metabolism during human diseases, in order to open new therapeutic perspectives in the treatment of pathophysiological angiogenesis, as in cancer.

The Metabolic Remodelling in Lung Cancer and Its Putative Consequence in Therapy Response.

Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women. Conventional chemotherapy has failed to provide long-term benefits for many patients and in the past decade, important advances were made to understand the underlying molecular/genetic mechanisms of lung cancer, allowing the unfolding of several other pathological entities. Considering these molecular subtypes, and the appearance of promising targeted therapies, an effective personalized control of the disease has emerged, nonetheless benefiting a small proportion of patients. Although immunotherapy has also appeared as a new hope, it is still not accessible to the majority of patients with lung cancer.The metabolism of energy and biomass is the basis of cellular survival. This is true for normal cells under physiological conditions and it is also true for pathophysiologically altered cells, such as cancer cells. Thus, knowledge of the metabolic remodelling that occurs in cancer cells in the sense of, on one hand, surviving in the microenvironment of the organ in which the tumour develops and, on the other hand, escaping from drugs conditioned microenvironment, is essential to understand the disease and to develop new therapeutic approaches.

Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer.

Metabolic remodeling is a critical skill of malignant cells, allowing their survival and spread. The metabolic dynamics and adaptation capacity of cancer cells allow them to escape from damaging stimuli, including breakage or cross-links in DNA strands and increased reactive oxygen species (ROS) levels, promoting resistance to currently available therapies, such as alkylating or oxidative agents. Therefore, it is essential to understand how metabolic pathways and the corresponding enzymatic systems can impact on tumor behavior. Cysteine aminotransferase (CAT) per se, as well as a component of the CAT: 3-mercaptopyruvate sulfurtransferase (MST) axis, is pivotal for this metabolic rewiring, constituting a central mechanism in amino acid metabolism and fulfilling the metabolic needs of cancer cells, thereby supplying other different pathways. In this review, we explore the current state-of-art on CAT function and its role on cancer cell metabolic rewiring as MST partner, and its relevance in cancer cells' fitness.

Acetylation drives hepatocyte nuclear factor 1ß stability by blocking proteasome-mediated degradation.

Hepatocyte nuclear factor 1ß (HNF1ß) is mostly expressed in the liver, but is also expressed in other organs, like kidney, pancreas and genitourinary tract. In fact, HNF1ß, a member of the superfamily of homeodomain-containing transcription factors, has been described as a hallmark in clear cell carcinomas. However, its role as an oncogene or as tumor suppressor gene remains controversial. Here, we disclose a mechanism of HNF1ß stabilization and degradation, using human HNF1ß-expressing cell lines of ovarian clear cell carcinoma (ES2), hepatocellular carcinoma (HEPG2), and normal immortalized kidney tubular cells (HK2). We show that increased levels of HNF1ß is concomitant with an increase in the acetylation load and protein stabilization by interfering with the ubiquitin-proteasome degradation system. This study reinforces that acetylation, besides their role in regulating chromatin conformation and gene expression, could also act in the action, turnover and stability of proteins essential for the survival and progression of certain cancer types.

l-Buthionine Sulfoximine Detection and Quantification in Polyurea Dendrimer Nanoformulations.

l-Buthionine sulfoximine (l-BSO) is an adjuvant drug that is reported to increase the sensitivity of cancer cells to neoplastic agents. Dendrimers are exceptional drug delivery systems and l-BSO nanoformulations are envisaged as potential chemotherapeutics. The absorption of l-BSO at a low wavelength limits its detection by conventional analytical tools. A simple and sensitive method for l-BSO detection and quantification is now reported. In this study, l-BSO was encapsulated in a folate-targeted generation four polyurea dendrimer (PUREG4-FA2) and its release profile was followed for 24 h at pH 7.4 and 37 °C. The protocol uses in situ l-BSO derivatization, by the formation of a catechol-derived orto-quinone, followed by visible detection of the derivative at 503 nm. The structure of the studied l-BSO derivative was assessed by NMR spectroscopy.

Cysteine boosters the evolutionary adaptation to CoCl2 mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer.

BACKGROUND: Ovarian cancer is the second most common gynaecologic malignancy and the most common cause of death from gynaecologic cancer, especially due to diagnosis at an advanced stage, when a cure is rare. As ovarian tumour grows, cancer cells are exposed to regions of hypoxia. Hypoxia is known to be partially responsible for tumour progression, metastasis and resistance to therapies. These suggest that hypoxia entails a selective pressure in which the adapted cells not only have a fitness increase under the selective environment, but also in non-selective adverse environments. In here, we used two different ovarian cancer cell lines - serous carcinoma (OVCAR3) and clear cell carcinoma (ES2) - in order to address the effect of cancer cells selection under normoxia and hypoxia mimicked by cobalt chloride on the evolutionary outcome of cancer cells. RESULTS: Our results showed that the adaptation to normoxia and CoCl2 mimicked hypoxia leads cells to display opposite strategies. Whereas cells adapted to CoCl2 mimicked hypoxia conditions tend to proliferate less but present increased survival in adverse environments, cells adapted to normoxia proliferate rapidly but at the cost of increased mortality in adverse environments. Moreover, results suggest that cysteine allows a quicker response and adaptation to hypoxic conditions that, in turn, are capable of driving chemoresistance. CONCLUSIONS: We showed that cysteine impacts the adaptation of cancer cells to a CoCl2 mimicked hypoxic environment thus contributing for hypoxia-drived platinum-based chemotherapeutic agents' resistance, allowing the selection of more aggressive phenotypes. These observations support a role of cysteine in cancer progression, recurrence and chemoresistance.

Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression.

The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.

Cysteine Oxidative Dynamics Underlies Hypertension and Kidney Dysfunction Induced by Chronic Intermittent Hypoxia.

Previous data showed the lack of efficacy of an adrenoceptor antagonist to revert hypertension induced by chronic intermittent hypoxia (CIH). We hypothesized that, in addition to sympathetic activation, CIH may change the availability and dynamics of cysteine. Temporal variation in total cysteine and its fractions, free reduced, free oxidized and protein-bound (CysSSP), were measured in homogenates of kidney cortex and medulla of Wistar rats. Animals were exposed to CIH for 14, 21 and 60 days and cysteine fractions and fibronectin gene expression were assessed at these time-points. Two different phases in cysteine dynamics were identified. An early phase (14d) characterized by an increase in cysteine oxidation and CysSSP forms. Late events (>21d) were characterized by a global reduction in cysteine, minimum level of CysSSP and maximum overexpression of fibronectin in kidney cortex. In conclusion, cysteine dynamics is influenced by the duration of CIH exposure: first there is a cysteine disulfide stress-like adaptive response followed by a progressive loss of cysteine availability and a decrease in CysSSP fraction. Kidney fibrosis associated to an unbalance in cysteine dynamics might contribute to the inefficacy of available antihypertensive drugs in patients with delayed diagnosis of sleep apnea.

Glutathione in Ovarian Cancer: A Double-Edged Sword.

Glutathione (GSH) has several roles in a cell, such as a reactive oxygen species (ROS) scavenger, an intervenient in xenobiotics metabolism and a reservoir of cysteine. All of these activities are important in the maintenance of normal cells homeostasis but can also constitute an advantage for cancer cells, allowing disease progression and resistance to therapy. Ovarian cancer is the major cause of death from gynaecologic disease and the second most common gynaecologic malignancy worldwide. In over 50 years, the overall survival of patients diagnosed with epithelial ovarian cancer has not changed, regardless of the efforts concerning early detection, radical surgery and new therapeutic approaches. Late diagnosis and resistance to therapy are the main causes of this outcome, and GSH is profoundly associated with chemoresistance to platinum salts, which, together with taxane-based chemotherapy and surgery, are the main therapy strategies in ovarian cancer treatment. Herein, we present some insights into the role of GSH in the poor prognosis of ovarian cancer, and also point out how some strategies underlying the dependence of ovarian cancer cells on GSH can be further used to improve the effectiveness of therapy.

HNF1ß drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC).

Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1ß (HNF1ß) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1ß, experiments were also performed in an OSC cell line, which does not express HNF1ß. Metabolic profiles, GSH quantification, HNF1ß, and γ-glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1ß knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1ß regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1ß as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC.

STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment.

Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer hallmark conditioned by the microenvironment. As uterine cervix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated with MCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ's microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.

Interaction between NSCLC Cells, CD8+ T-Cells and Immune Checkpoint Inhibitors Potentiates Coagulation and Promotes Metabolic Remodeling-New Cues on CAT-VTE.

BACKGROUND: Cancer-associated thrombosis (CAT) and venous thromboembolism (VTE) are frequent cancer-related complications associated with high mortality; thus, this urges the identification of predictive markers. Immune checkpoint inhibitors (ICIs) used in cancer immunotherapy allow T-cell activation against cancer cells. Retrospective studies showed increased VTE following ICI administration in some patients. Non-small cell lung cancer (NSCLC) patients are at high risk of thrombosis and thus, the adoption of immunotherapy, as a first-line treatment, seems to be associated with coagulation-fibrinolysis derangement. METHODS: We pharmacologically modulated NSCLC cell lines in co-culture with CD8+ T-cells (TCD8+) and myeloid-derived suppressor cells (MDSCs), isolated from healthy blood donors. The effects of ICIs Nivolumab and Ipilimumab on NSCLC cell death were assessed by annexin V and propidium iodide (PI) flow cytometry analysis. The potential procoagulant properties were analyzed by in vitro clotting assays and enzyme-linked immunosorbent assays (ELISAs). The metabolic remodeling induced by the ICIs was explored by 1H nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Flow cytometry analysis showed that TCD8+ and ICIs increase cell death in H292 and PC-9 cells but not in A549 cells. Conditioned media from NSCLC cells exposed to TCD8+ and ICI induced in vitro platelet aggregation. In A549, Podoplanin (PDPN) levels increased with Nivolumab. In H292, ICIs increased PDPN levels in the absence of TCD8+. In PC-9, Ipilimumab decreased PDPN levels, this effect being rescued by TCD8+. MDSCs did not interfere with the effect of TCD8+ in the production of TF or PDPN in any NSCLC cell lines. The exometabolome showed a metabolic remodeling in NSCLC cells upon exposure to TCD8+ and ICIs. CONCLUSIONS: This study provides some insights into the interplay of immune cells, ICIs and cancer cells influencing the coagulation status. ICIs are important promoters of coagulation, benefiting from TCD8+ mediation. The exometabolome analysis highlighted the relevance of acetate, pyruvate, glycine, glutamine, valine, leucine and isoleucine as biomarkers. Further investigation is needed to validate this finding in a cohort of NSCLC patients.

Metabolic profiling and combined therapeutic strategies unveil the cytotoxic potential of selenium-chrysin (SeChry) in NSCLC cells.

Lung cancer ranks as the predominant cause of cancer-related mortalities on a global scale. Despite progress in therapeutic interventions, encompassing surgical procedures, radiation, chemotherapy, targeted therapies and immunotherapy, the overall prognosis remains unfavorable. Imbalances in redox equilibrium and disrupted redox signaling, common traits in tumors, play crucial roles in malignant progression and treatment resistance. Cancer cells, often characterized by persistent high levels of reactive oxygen species (ROS) resulting from genetic, metabolic, and microenvironmental alterations, counterbalance this by enhancing their antioxidant capacity. Cysteine availability emerges as a critical factor in chemoresistance, shaping the survival dynamics of non­small cell lung cancer (NSCLC) cells. Selenium-chrysin (SeChry) was disclosed as a modulator of cysteine intracellular availability. This study comprehensively characterizes the metabolism of SeChry and investigates its cytotoxic effects in NSCLC. SeChry treatment induces notable metabolic shifts, particularly in selenocompound metabolism, impacting crucial pathways such as glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Additionally, SeChry affects the levels of key metabolites such as acetate, lactate, glucose, and amino acids, contributing to disruptions in redox homeostasis and cellular biosynthesis. The combination of SeChry with other treatments, such as glycolysis inhibition and chemotherapy, results in greater efficacy. Furthermore, by exploiting NSCLC's capacity to consume lactate, the use of lactic acid-conjugated dendrimer nanoparticles for SeChry delivery is investigated, showing specificity to cancer cells expressing monocarboxylate transporters.

BRD9 status is a major contributor for cysteine metabolic remodeling through MST and EAAT3 modulation in malignant melanoma.

Cutaneous melanoma (CM) is the most aggressive skin cancer, showing globally increasing incidence. Hereditary CM accounts for a significant percentage (5-15 %) of all CM cases. However, most familial cases remain without a known genetic cause. Even though, BRD9 has been associated to CM as a susceptibility gene. The molecular events following BRD9 mutagenesis are still not completely understood. In this study, we disclosed BRD9 as a key regulator in cysteine metabolism and associated altered BRD9 to increased cell proliferation, migration and invasiveness, as well as to altered melanin levels, inducing higher susceptibility to melanomagenesis. It is evident that BRD9 WT and mutated BRD9 (c.183G>C) have a different impact on cysteine metabolism, respectively by inhibiting and activating MPST expression in the metastatic A375 cell line. The effect of the mutated BRD9 variant was more evident in A375 cells than in the less invasive WM115 line. Our data point out novel molecular and metabolic mechanisms dependent on BRD9 status that potentially account for the increased risk of developing CM and enhancing CM aggressiveness. Moreover, our findings emphasize the role of cysteine metabolism remodeling in melanoma progression and open new queues to follow to explore the role of BRD9 as a melanoma susceptibility or cancer-related gene.

An integrative view on glucagon function and putative role in the progression of pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC).

Cancer metabolism research area evolved greatly, however, is still unknown the impact of systemic metabolism control and diet on cancer. It makes sense that systemic regulators of metabolism can act directly on cancer cells and activate signalling, prompting metabolic remodelling needed to sustain cancer cell survival, tumour growth and disease progression. In the present review, we describe the main glucagon functions in the control of glycaemia and of metabolic pathways overall. Furthermore, an integrative view on how glucagon and related signalling pathways can contribute for pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC) progression, since pancreas and liver are the major organs exposed to higher levels of glucagon, pancreas as a producer and liver as a scavenger. The main objective is to bring to discussion some glucagon-dependent mechanisms by presenting an integrative view on microenvironmental and systemic aspects in pNETs and HCC biology.