COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated ...in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.
Abstract Fibroblasts are the most abundant “non-cancerous” cells in tumors. However, it remains largely unknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, ...driving chemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAF signaling pathways and their emerging metabolic phenotypes that promote tumor growth. Although it is well established that altered cancer metabolism enhances tumor growth, little is known about the role of fibroblast metabolism in tumor growth. New studies reveal that metabolic coupling occurs between catabolic fibroblasts and anabolic cancer cells, in many types of human tumors, including breast, prostate, and head & neck cancers, as well as lymphomas. These catabolic phenotypes observed in CAFs are secondary to a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NFκB signaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. These catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support tumor growth, via the local stromal generation of mitochondrial fuels (lactate, ketone bodies, fatty acids, glutamine, and other amino acids). New biomarkers of this catabolic CAF phenotype (such as caveolin-1 (Cav-1) and MCT4), which are reversible upon treatment with anti-oxidants, are strong predictors of poor clinical outcome in various types of human cancers. How cancer cells metabolically reprogram fibroblasts can also help us to understand the effects of cancer cells at an organismal level, explaining para-neoplastic phenomena, such as cancer cachexia. In conclusion, cancer should be viewed more as a systemic disease, that engages the host-organism in various forms of energy-transfer and metabolic co-operation, across a whole-body “ecosystem”.
Cancer metabolism: a therapeutic perspective Martinez-Outschoorn, Ubaldo E; Peiris-Pagés, Maria; Pestell, Richard G ...
Nature reviews. Clinical oncology,
01/2017, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour cells metabolize glucose, ...lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction-oxidation (redox) balance and committing resources to biosynthesis - processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and normal cells holds promise as a novel anticancer strategy. In this Review, we discuss how cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression; in particular, we highlight potential metabolic vulnerabilities that might be targeted therapeutically.
Metabolic synergy or metabolic coupling between glycolytic stromal cells (Warburg effect) and oxidative cancer cells occurs in human breast cancers and promotes tumor growth. The Warburg effect or ...aerobic glycolysis is the catabolism of glucose to lactate to obtain adenosine triphosphate (ATP). This review summarizes the main findings on this stromal metabolic phenotype, and the associated signaling pathways, as well as the critical role of oxidative stress and autophagy, all of which promote carcinoma cell mitochondrial metabolism and tumor growth. Loss of Caveolin 1 (Cav-1) and the upregulation of monocarboxylate transporter 4 (MCT4) in stromal cells are novel markers of the Warburg effect and metabolic synergy between stromal and carcinoma cells. MCT4 and Cav-1 are also breast cancer prognostic biomarkers. Reactive oxygen species (ROS) are key mediators of the stromal Warburg effect. High ROS also favors cancer cell mitochondrial metabolism and tumorigenesis, and anti-oxidants can reverse this altered stromal and carcinoma metabolism. A pseudo-hypoxic state with glycolysis and low mitochondrial metabolism in the absence of hypoxia is a common feature in breast cancer. High ROS induces loss of Cav-1 in stromal cells and is sufficient to generate a pseudo-hypoxic state. Loss of Cav-1 in the stroma drives glycolysis and lactate extrusion via HIF-1α stabilization and the upregulation of MCT4. Stromal cells with loss of Cav-1 and/or high expression of MCT4 also show a catabolic phenotype, with enhanced macroautophagy. This catabolic state in stromal cells is driven by hypoxia-inducible factor (HIF)-1α, nuclear factor κB (NFκB), and JNK activation and high ROS generation. A feed-forward loop in stromal cells regulates pseudo-hypoxia and metabolic synergy, with Cav-1, MCT4, HIF-1α, NFκB, and ROS as its key elements. Metabolic synergy also may occur between cancer cells and cells in distant organs from the tumor. Cancer cachexia, which is due to severe organismal metabolic dysregulation in myocytes and adipocytes, shares similarities with stromal-carcinoma metabolic synergy, as well. In summary, metabolic synergy occurs when breast carcinoma cells induce a nutrient-rich microenvironment to promote tumor growth. The process of tumor metabolic synergy is a multistep process, due to the generation of ROS, and the induction of catabolism with autophagy, mitophagy and glycolysis. Studying epithelial-stromal interactions and metabolic synergy is important to better understand the ecology of cancer and the metabolic role of different cell types in tumor progression.
Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells ...(TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect". Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.
Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and ...distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic breast cancer patient samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as aldehyde dehydrogenase (ALDH) activity, and they were ESA+/CD24-/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2-fold increase in mitochondrial mass in large cells (>12-μm), relative to the smaller cell population (4-8-μm). Moreover, the mito-high cell population showed a 2.4-fold enrichment in tumor-initiating cell activity, based on limiting dilution assays in murine xenografts. Importantly, primary human breast CSCs isolated from patients with metastatic breast cancer or a patient derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to paclitaxel, resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub-population of breast cancer cells confers a stem-like phenotype and chemo-resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population.
The functional role of oxidative stress in cancer pathogenesis has long been a hotly debated topic. A study published this month in BMC Cancer by Goh et al., directly addresses this issue by using a ...molecular genetic approach, via an established mouse animal model of human breast cancer. More specifically, alleviation of mitochondrial oxidative stress, via transgenic over-expression of catalase (an anti-oxidant enzyme) targeted to mitochondria, was sufficient to lower tumor grade (from high-to-low) and to dramatically reduce metastatic tumor burden by >12-fold. Here, we discuss these new findings and place them in the context of several other recent studies showing that oxidative stress directly contributes to tumor progression and metastasis. These results have important clinical and translational significance, as most current chemo-therapeutic agents and radiation therapy increase oxidative stress, and, therefore, could help drive tumor recurrence and metastasis. Similarly, chemo- and radiation-therapy both increase the risk for developing a secondary malignancy, such as leukemia and/or lymphoma. To effectively reduce mitochondrial oxidative stress, medical oncologists should now re-consider the use of powerful anti-oxidants as a key component of patient therapy and cancer prevention. Please see related research article: http://www.biomedcentral.com/1471-2407/11/191.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Caveolae and signalling in cancer Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P
Nature reviews. Cancer,
04/2015, Letnik:
15, Številka:
4
Journal Article
Recenzirano
Odprti dostop
It has been over 20 years since the discovery that caveolar lipid rafts function as signalling organelles. Lipid rafts create plasma membrane heterogeneity, and caveolae are the most extensively ...studied subset of lipid rafts. A newly emerging paradigm is that changes in caveolae also generate tumour metabolic heterogeneity. Altered caveolae create a catabolic tumour microenvironment, which supports oxidative mitochondrial metabolism in cancer cells and which contributes to dismal survival rates for cancer patients. In this Review, we discuss the role of caveolae in tumour progression, with a special emphasis on their metabolic and cell signalling effects, and their capacity to transform the tumour microenvironment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Cancer cells recruit normal cells such as fibroblasts to establish reactive microenvironments. Via metabolic stress, catabolism and inflammation, these cancer-associated fibroblasts set up a ...synergistic relationship with tumour cells, that contributes to their malignancy and resistance to therapy. Given that chemotherapy is a systemic treatment, the possibility that healthy cell damage affects the metastatic risk or the prospect of developing a second malignancy becomes relevant. Here, we demonstrate that standard chemotherapies phenotypically and metabolically transform stromal fibroblasts into cancer-associated fibroblasts, leading to the emergence of a highly glycolytic, autophagic and pro-inflammatory microenvironment. This catabolic microenvironment, in turn, activates stemness (Sonic hedgehog/GLI signalling), antioxidant response and interferon-mediated signalling, in adjacent breast cancer cells. Thus, we propose a model by which chemotherapy-induced catabolism in healthy fibroblasts constitutes a source of energy-rich nutrients and inflammatory cytokines that would activate stemness in adjacent epithelial cells, possibly triggering new tumorigenic processes. In this context, immune cell recruitment would be also stimulated to further support malignancy.
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