6068 Background: Durvalumab is a human monoclonal IgG1 antibody directed against programmed death... more 6068 Background: Durvalumab is a human monoclonal IgG1 antibody directed against programmed death-ligand 1 (PD-L1). PD-1/PD-L1 immune checkpoint inhibition (ICI) shows promise in HNSCC, but durable responses have been seen in only a fraction of patients. Metformin, a biguanide oral anti-hyperglycemic, has shown promise in altering immunity within the tumor microenvironment (TME) towards a stronger anti-tumor distribution of immune cells. We aimed to investigate the combined effect of metformin and durvalumab in patients with HNSCC. Methods: This was a single-center prospective phase 1, window of opportunity clinical trial in which previously untreated patients with any stage resectable HNSCC were randomized 3:1 to durvalumab + metformin (Arm A) or durvalumab alone (Arm B) during a four-week period between diagnosis and surgical resection. Six patients were included in a safety lead-in of durvalumab and metformin and an additional 32 patients were randomized. The primary endpoint was...
Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lac... more Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured...
Background. End-stage renal disease (ESRD) is associated with inflammation and increased reactive... more Background. End-stage renal disease (ESRD) is associated with inflammation and increased reactive oxygen species (ROS). Inflammation and oxidative stress are associated with several complications of ESRD. The aim of this study was to determine histological characteristics of adipose tissue and muscle mitochondrial function in uremia and its relationship with inflammation. Methods. ESRD patients (n ¼ 18) and controls (n ¼ 6) were enrolled for studies of adipose and muscle tissue by immunohistochemistry and western blot. In a uremic muscle cell model, C2C12 cells were exposed to uremic serum and inflammatory cytokines. Mitochondrial function was studied by MitoTracker Orange, translocase of the mitochondrial outer membrane 20 (TOMM20) and mitochondrial oxidative phosphorylation complex subunit expression. Results. ESRD patients had increased macrophage infiltration in subcutaneous and visceral adipose tissue compared with controls, even in nonobese ESRD patients (P < 0.05). Compared with controls, TOMM20 expression in muscle tissue was lower in ESRD, consistent with reduced mitochondrial function (P < 0.05). C2C12 exposed to uremia had decreased mitotracker intensity (P < 0.05) and the reduced mitochondrial function was rescued by N-acetyl cysteine (P < 0.01). Similarly, C2C12 cells exposed to tumor necrosis factor a (TNF-a)/interleukin-6 (IL-6) have decreased mitotracker intensity (P < 0.01) that was rescued with adiponectin (P < 0.05). C2C12 exposed to TNF-a, IL-6 and buthionine sulfoximine had decreased TOMM20 expression and cells exposed to TNF-a showed a decrease in subunits of mitochondrial complexes I and III. Conclusion. Our data indicate that uremia is associated with increased adipose tissue macrophage infiltration and concurrent muscle tissue mitochondrial dysfunction induced by inflammation/ROS. Adipose tissue is a potential source of inflammation in ESRD that is not due to increased adiposity and may contribute to mitochondrial dysfunction in uremia.
The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to... more The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors. Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. Fifty patients were enrolled, and 39 completed a full-treatment course. Metformin was titrated to standard diabetic dose (2,000 mg/day) for a course of 9 or more days prior to surgery. Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB), and monocarboxylate transporter 4 (MCT4), as well as the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)...
The Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol synthesis caused by... more The Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol synthesis caused by mutations in DHCR7 which encodes the final enzyme in the cholesterol synthesis pathway. The immediate precursor to cholesterol synthesis, 7-dehydrocholesterol (7-DHC) accumulates in the plasma and cells of SLOS patients which has led to the idea that the accumulation of abnormal sterols and/or reduction in cholesterol underlies the phenotypic abnormalities of SLOS. We tested the hypothesis that 7-DHC accumulates in membrane caveolae where it disturbs caveolar bilayer structure-function. Membrane caveolae from skin fibroblasts obtained from SLOS patients were isolated and found to accumulate 7-DHC. In caveolar-like model membranes containing 7-DHC, subtle, but complex alterations in intermolecular packing, lipid order and membrane width were observed. In addition, the BK Ca K + channel, which co-migrates with caveolin-1 in a membrane fraction enriched with cholesterol, was impaired in SLOS cells as reflected by reduced single channel conductance and a 50 mV rightward shift in the channel activation voltage. In addition, a
The International Journal of Biochemistry & Cell Biology, 2009
It has been previously shown that PPARγ ligands induce apoptotic cell death in a variety of cance... more It has been previously shown that PPARγ ligands induce apoptotic cell death in a variety of cancer cells. Given the evidence that these ligands have a receptor-independent function, we further examined the specific role of PPARγ activation in this biological process. Surprisingly, we failed to demonstrate that MDA-MB-231 breast cancer cells undergo apoptosis when treated with subsaturation doses of troglitazone and rosiglitazone, which are synthetic PPARγ ligands. Acridine orange (AO) staining showed acidic vesicular formation within ligand-treated cells, indicative of autophagic activity. This was confirmed by autophagosome formation as indicated by redistribution of LC3, an autophagy-specific protein, and the appearance of double-membrane autophagic vacuoles by electron microscopy following exposure to ligand. To determine the mechanism by which PPARγ induces autophagy, we transduced primary mammary epithelial cells with a constitutively active mutant of PPARγ and screened gene expression associated with PPARγ activation by genomewide array analysis. HIF1α and BNIP3 were among 42 genes up-regulated by active PPARγ. Activation of PPARγ induced HIF1α and BNIP3 protein and mRNA abundance. HIF1α knockdown by shRNA abolished the autophagosome formation induced by PPARγ activation. In summary, our data shows a specific induction of autophagy by PPARγ activation in breast cancer cells providing an understanding of distinct roles of PPARγ in tumorigenesis.
The normal gene expression profile of rete-tip keratinocytes targeted in human graft-versus-host ... more The normal gene expression profile of rete-tip keratinocytes targeted in human graft-versus-host disease (GVHD) remains unexplored. Murine lingual epithelium, unlike murine skin, consists of a basal layer that resembles human cutaneous rete ridges and harbors rete tip-associated cells that express cytokeratin 15 (K15), a marker for epithelial stem cells. Target cell apoptosis in murine GVHD preferentially involves subpopulations of basal cells that (1) reside at tips of lingual rete ridge-like prominences (RLPs), (2) constitutively express K15 protein, (3) express the proapoptotic protein Bax early in disease progression, and (4) coincide spatially with putative epithelial stem cells. Here, we show by real-time reverse transcription-PCR that immunohistochemistry-guided laser-captured K15-positive (K15 þ) murine basal cells constitutively express quantitatively higher mRNA levels for K15 but lower mRNA levels of Bax than do K15 À basal cells, consistent with the presumed stem cell nature of K15 þ basal cells. Moreover, apoptosis gene array screening of K15 þ microdissected basal cells demonstrated a dominant trend toward the preferential expression of genes associated with protection from apoptosis. Accordingly, genes that regulate apoptotic vulnerability are differentially expressed in basal layer subpopulations distinguishable by K15 expression.
the role of ppARγ in cancer therapy is controversial, with studies showing either pro-tumorigenic... more the role of ppARγ in cancer therapy is controversial, with studies showing either pro-tumorigenic or antineoplastic effects. this debate is very clinically relevant, because ppARγ agonists are used as antidiabetic drugs. Here, we evaluated if the effects of ppARγ on tumorigenesis are determined by the cell type in which ppARγ is activated. Second, we examined if the metabolic changes induced by ppARγ, such as glycolysis and autophagy, play any role in the tumorigenic process. to this end, ppARγ was overexpressed in breast cancer cells or in stromal cells. ppARγ-overexpressing cells were examined with respect to (1) their tumorigenic potential, using xenograft models, and (2) regarding their metabolic features. In xenograft models, we show that when ppARγ is activated in cancer cells, tumor growth is inhibited by 40%. However, when ppARγ is activated in stromal cells, the growth of co-injected breast cancer cells is enhanced by 60%. thus, the effect(s) of ppARγ on tumorigenesis are dependent on the cell compartment in which ppARγ is activated. Mechanistically, stromal cells with activated ppARγ display metabolic features of cancer-associated fibroblasts, with increased autophagy, glycolysis and senescence. Indeed, fibroblasts overexpressing ppARγ show increased expression of autophagic markers, increased numbers of acidic autophagic vacuoles, increased production of L-lactate, cell hypertrophy and mitochondrial dysfunction. In addition, ppARγ fibroblasts show increased expression of CDKs (p16/p21) and β-galactosidase, which are markers of cell cycle arrest and senescence. Finally, ppARγ induces the activation of the two major transcription factors that promote autophagy and glycolysis, i.e., HIF-1α and NFκB, in stromal cells. thus, ppARγ activation in stromal cells results in the formation of a catabolic pro-inflammatory microenvironment that metabolically supports cancer growth. Interestingly, the tumor inhibition observed when ppARγ is expressed in epithelial cancer cells is also associated with increased autophagy, suggesting that activation of an autophagic program has both pro-or antitumorigenic effects depending on the cell compartment in which it occurs. Finally, when ppARγ is expressed in epithelial cancer cells, the suppression of tumor growth is associated with a modest inhibition of angiogenesis. In conclusion, these data support the "two-compartment tumor metabolism" model, which proposes that metabolic coupling exists between catabolic stromal cells and oxidative cancer cells. Cancer cells induce autophagy, glycolysis and senescence in stromal cells. In return, stromal cells generate onco-metabolites and mitochondrial fuels (L-lactate, ketones, glutamine/aminoacids and fatty acids) that are used by cancer cells to enhance their tumorigenic potential. thus, as researchers design new therapies, they must be conscious that cancer is not a cell-autonomous disease, but rather a tumor is an ecosystem of many different cell types, which engage in metabolic symbiosis.
Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different met... more Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (oXpHoS) and the uptake of mitochondrial fuels, as detected via MCt1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/toMM20+/CoX+/MCt1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67−/toMM20−/CoX−/MCt1−); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67−/toMM20−/CoX−/MCt1−). In addition, high oxidative stress (MCt4+) was very specific for cancer tissues. thus, we next evaluated the prognostic value of MCt4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCt4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-pet avidity (p < 0.04). Similarly, oxidative stress (MCt4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCt4 inhibitors should be developed to metabolically target "three-compartment tumor metabolism" in head and neck cancers. It is remarkable that two "non-proliferating" populations of cells (Ki-67−/MCt4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial "fuels" for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial "stem cell" layer is hyper-proliferative (Ki-67+), mitochondrialrich (toMM20+/CoX+) and is metabolically programmed to use mitochondrial fuels (MCt1+), such as ketone bodies and L-lactate. thus, oxidative mitochondrial metabolism (oXpHoS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCt1 and MCt4 inhibitors, to target "metabolic symbiosis."
Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains lar... more Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTeRT-BJ1) were stably transfected with autophagy genes (BNIp3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed features of senescence, with increased p21(WAF1/CIp1), a CDK inhibitor, cellular hypertrophy and increased β-galactosidase activity. Thus, we genetically validated the existence of the autophagy-senescence transition. Importantly, autophagic-senescent fibroblasts promoted tumor growth and metastasis, when co-injected with human breast cancer cells, independently of angiogenesis. Autophagic-senescent fibroblasts stimulated mitochondrial metabolism in adjacent cancer cells, when the two cell types were co-cultured, as visualized by MitoTracker staining. In particular, autophagic ATG16L1 fibroblasts, which produced large amounts of ketone bodies (3-hydroxy-butyrate), had the strongest effects and promoted metastasis by up to 11-fold. Conversely, expression of ATG16L1 in epithelial cancer cells inhibited tumor growth, indicating that the effects of autophagy are compartment-specific. Thus, autophagic-senescent fibroblasts metabolically promote tumor growth and metastasis, by paracrine production of high-energy mitochondrial fuels. Our current studies provide genetic support for the importance of "two-compartment tumor metabolism" in driving tumor growth and metastasis via a simple energy transfer mechanism. Finally, β-galactosidase, a known lysosomal enzyme and biomarker of senescence, was localized to the tumor stroma in human breast cancer tissues, providing in vivo support for our hypothesis. Bioinformatic analysis of genome-wide transcriptional profiles from tumor stroma, isolated from human breast cancers, also validated the onset of an autophagy-senescence transition. Taken together, these studies establish a new functional link between host aging, autophagy, the tumor microenvironment and cancer metabolism.
We and others have recently shown that a loss of caveolin-1 (Cav-1) in stromal cells is a predict... more We and others have recently shown that a loss of caveolin-1 (Cav-1) in stromal cells is a predictor of early tumor recurrence, lymph node metastasis, tamoxifen resistance and poor clinical outcome in human breast cancer patients. 2,3 To investigate the downstream effects of a loss of stromal Cav-1, we isolated bone marrow-derived stromal cells from WT and Cav-1(-/-)-null mice and subjected them to metabolomic and proteomic analyses and genome-wide transcriptional profiling. Interestingly, Cav-1(-/-)
Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. ... more Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCt4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. to address this issue, we cocultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCt4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCt4. We also show that the expression of MCt4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCt4, we see that MCt1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCt4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCt1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCt4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. these data are consistent with the "reverse Warburg effect," which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, "energy transfer" or "metabolic-coupling" between the tumor stroma and epithelial cancer cells "fuels" tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCt inhibitors.
We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast ... more We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive tGF-β signaling. However, it remains unknown whether hyperactivation of the tGF-β signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. to address these issues, we overexpressed tGF-β ligands and the tGF-β receptor I (tGF-β-RI) in stromal fibroblasts and breast cancer cells. Here, we show that the role of tGF-β in tumorigenesis is compartment-specific, and that tGF-β promotes tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the tumorpromoting effects of tGF-β are independent of the cell type generating tGF-β. thus, stromal-derived tGF-β activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that tGF-β-activated fibroblasts promote the mitochondrial activity of adjacent cancer cells, and in a xenograft model, enhancing the growth of breast cancer cells, independently of angiogenesis. Conversely, activation of the tGF-β pathway in cancer cells does not influence tumor growth, but cancer cell-derived-tGF-β ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced tumor growth. In conclusion, ligand-dependent or cellautonomous activation of the tGF-β pathway in stromal cells induces their metabolic reprogramming, with increased oxidative stress, autophagy/mitophagy and glycolysis, and downregulation of Cav-1. these metabolic alterations can spread among neighboring fibroblasts and greatly sustain the growth of breast cancer cells. our data provide novel insights into the role of the tGF-β pathway in breast tumorigenesis, and establish a clear causative link between the tumor-promoting effects of tGF-β signaling and the metabolic reprogramming of the tumor microenvironment.
enzymes for energy production, via oxidative phosphorylation. During this process (OXPHOS), react... more enzymes for energy production, via oxidative phosphorylation. During this process (OXPHOS), reactive oxygen species (ROS) are generated as by-products of the reduction of molecular oxygen to water. In addition to ROS, the mitochondrial respiratory chain can also produce nitric oxide, which is another free radical F.S. and her laboratory were supported by grants from the Breast Cancer Alliance (BCA) and the American Cancer Society (ACS).
We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In... more We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In this scenario, cancer cells behave as metabolic parasites, by extracting nutrients from normal host cells, such as fibroblasts, via the secretion of hydrogen peroxide as the initial trigger. oxidative stress in the tumor microenvironment then leads to autophagy-driven catabolism, mitochondrial dys-function and aerobic glycolysis. this, in turn, produces high-energy nutrients (such as L-lactate, ketones and glutamine) that drive the anabolic growth of tumor cells, via oxidative mitochondrial metabolism. a logical prediction of this new "parasitic" cancer model is that tumor-associated fibroblasts should show evidence of mitochondrial dys-function (mitophagy and aerobic glycolysis). In contrast, epithelial cancer cells should increase their oxidative mitochondrial capacity. to further test this hypothesis, here we subjected frozen sections from human breast tumors to a staining procedure that only detects functional mitochondria. this method detects the in situ enzymatic activity of cytochrome C oxidase (CoX), also known as Complex IV. Remarkably, cancer cells show an overabundance of CoX activity, while adjacent stromal cells remain essentially negative. adjacent normal ductal epithelial cells also show little or no CoX activity, relative to epithelial cancer cells. thus, oxidative mitochondrial activity is selectively amplified in cancer cells. although CoX activity staining has never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. similar results were obtained with NaDh activity staining, which measures Complex I activity, and succinate dehydrogenase (sDh) activity staining, which measures Complex II activity. CoX and NaDh activities were blocked by electron transport inhibitors, such as Metformin. this has mechanistic and clinical implications for using Metformin as an anti-cancer drug, both for cancer therapy and chemo-prevention. We also immuno-stained human breast cancers for a series of well-established protein biomarkers of metabolism. More specifically, we now show that cancer-associated fibroblasts overexpress markers of autophagy (cathepsin B), mitophagy (BNIp3L) and aerobic glycolysis (MCt4). Conversely, epithelial cancer cells show the overexpression of a mitochondrial membrane marker (toMM20), as well as key components of Complex IV (Mt-Co1) and Complex II (sDh-B). We also validated our observations using a bioinformatics approach with data from >2,000 breast cancer patients, which showed the transcriptional upregulation of mitochondrial oxidative phosphorylation (oXphos) in human breast tumors (p < 10-20), and a specific association with metastasis. therefore, upregulation of oXphos in epithelial tumor cells is a common feature of human breast cancers. In summary, our data provide the first functional in vivo evidence that epithelial cancer cells perform enhanced mitochondrial oxidative phosphorylation, allowing them to produce high amounts of atp. thus, we believe that mitochondria are both the "powerhouse" and "achilles' heel" of cancer cells.
6068 Background: Durvalumab is a human monoclonal IgG1 antibody directed against programmed death... more 6068 Background: Durvalumab is a human monoclonal IgG1 antibody directed against programmed death-ligand 1 (PD-L1). PD-1/PD-L1 immune checkpoint inhibition (ICI) shows promise in HNSCC, but durable responses have been seen in only a fraction of patients. Metformin, a biguanide oral anti-hyperglycemic, has shown promise in altering immunity within the tumor microenvironment (TME) towards a stronger anti-tumor distribution of immune cells. We aimed to investigate the combined effect of metformin and durvalumab in patients with HNSCC. Methods: This was a single-center prospective phase 1, window of opportunity clinical trial in which previously untreated patients with any stage resectable HNSCC were randomized 3:1 to durvalumab + metformin (Arm A) or durvalumab alone (Arm B) during a four-week period between diagnosis and surgical resection. Six patients were included in a safety lead-in of durvalumab and metformin and an additional 32 patients were randomized. The primary endpoint was...
Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lac... more Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured...
Background. End-stage renal disease (ESRD) is associated with inflammation and increased reactive... more Background. End-stage renal disease (ESRD) is associated with inflammation and increased reactive oxygen species (ROS). Inflammation and oxidative stress are associated with several complications of ESRD. The aim of this study was to determine histological characteristics of adipose tissue and muscle mitochondrial function in uremia and its relationship with inflammation. Methods. ESRD patients (n ¼ 18) and controls (n ¼ 6) were enrolled for studies of adipose and muscle tissue by immunohistochemistry and western blot. In a uremic muscle cell model, C2C12 cells were exposed to uremic serum and inflammatory cytokines. Mitochondrial function was studied by MitoTracker Orange, translocase of the mitochondrial outer membrane 20 (TOMM20) and mitochondrial oxidative phosphorylation complex subunit expression. Results. ESRD patients had increased macrophage infiltration in subcutaneous and visceral adipose tissue compared with controls, even in nonobese ESRD patients (P < 0.05). Compared with controls, TOMM20 expression in muscle tissue was lower in ESRD, consistent with reduced mitochondrial function (P < 0.05). C2C12 exposed to uremia had decreased mitotracker intensity (P < 0.05) and the reduced mitochondrial function was rescued by N-acetyl cysteine (P < 0.01). Similarly, C2C12 cells exposed to tumor necrosis factor a (TNF-a)/interleukin-6 (IL-6) have decreased mitotracker intensity (P < 0.01) that was rescued with adiponectin (P < 0.05). C2C12 exposed to TNF-a, IL-6 and buthionine sulfoximine had decreased TOMM20 expression and cells exposed to TNF-a showed a decrease in subunits of mitochondrial complexes I and III. Conclusion. Our data indicate that uremia is associated with increased adipose tissue macrophage infiltration and concurrent muscle tissue mitochondrial dysfunction induced by inflammation/ROS. Adipose tissue is a potential source of inflammation in ESRD that is not due to increased adiposity and may contribute to mitochondrial dysfunction in uremia.
The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to... more The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors. Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. Fifty patients were enrolled, and 39 completed a full-treatment course. Metformin was titrated to standard diabetic dose (2,000 mg/day) for a course of 9 or more days prior to surgery. Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB), and monocarboxylate transporter 4 (MCT4), as well as the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)...
The Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol synthesis caused by... more The Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol synthesis caused by mutations in DHCR7 which encodes the final enzyme in the cholesterol synthesis pathway. The immediate precursor to cholesterol synthesis, 7-dehydrocholesterol (7-DHC) accumulates in the plasma and cells of SLOS patients which has led to the idea that the accumulation of abnormal sterols and/or reduction in cholesterol underlies the phenotypic abnormalities of SLOS. We tested the hypothesis that 7-DHC accumulates in membrane caveolae where it disturbs caveolar bilayer structure-function. Membrane caveolae from skin fibroblasts obtained from SLOS patients were isolated and found to accumulate 7-DHC. In caveolar-like model membranes containing 7-DHC, subtle, but complex alterations in intermolecular packing, lipid order and membrane width were observed. In addition, the BK Ca K + channel, which co-migrates with caveolin-1 in a membrane fraction enriched with cholesterol, was impaired in SLOS cells as reflected by reduced single channel conductance and a 50 mV rightward shift in the channel activation voltage. In addition, a
The International Journal of Biochemistry & Cell Biology, 2009
It has been previously shown that PPARγ ligands induce apoptotic cell death in a variety of cance... more It has been previously shown that PPARγ ligands induce apoptotic cell death in a variety of cancer cells. Given the evidence that these ligands have a receptor-independent function, we further examined the specific role of PPARγ activation in this biological process. Surprisingly, we failed to demonstrate that MDA-MB-231 breast cancer cells undergo apoptosis when treated with subsaturation doses of troglitazone and rosiglitazone, which are synthetic PPARγ ligands. Acridine orange (AO) staining showed acidic vesicular formation within ligand-treated cells, indicative of autophagic activity. This was confirmed by autophagosome formation as indicated by redistribution of LC3, an autophagy-specific protein, and the appearance of double-membrane autophagic vacuoles by electron microscopy following exposure to ligand. To determine the mechanism by which PPARγ induces autophagy, we transduced primary mammary epithelial cells with a constitutively active mutant of PPARγ and screened gene expression associated with PPARγ activation by genomewide array analysis. HIF1α and BNIP3 were among 42 genes up-regulated by active PPARγ. Activation of PPARγ induced HIF1α and BNIP3 protein and mRNA abundance. HIF1α knockdown by shRNA abolished the autophagosome formation induced by PPARγ activation. In summary, our data shows a specific induction of autophagy by PPARγ activation in breast cancer cells providing an understanding of distinct roles of PPARγ in tumorigenesis.
The normal gene expression profile of rete-tip keratinocytes targeted in human graft-versus-host ... more The normal gene expression profile of rete-tip keratinocytes targeted in human graft-versus-host disease (GVHD) remains unexplored. Murine lingual epithelium, unlike murine skin, consists of a basal layer that resembles human cutaneous rete ridges and harbors rete tip-associated cells that express cytokeratin 15 (K15), a marker for epithelial stem cells. Target cell apoptosis in murine GVHD preferentially involves subpopulations of basal cells that (1) reside at tips of lingual rete ridge-like prominences (RLPs), (2) constitutively express K15 protein, (3) express the proapoptotic protein Bax early in disease progression, and (4) coincide spatially with putative epithelial stem cells. Here, we show by real-time reverse transcription-PCR that immunohistochemistry-guided laser-captured K15-positive (K15 þ) murine basal cells constitutively express quantitatively higher mRNA levels for K15 but lower mRNA levels of Bax than do K15 À basal cells, consistent with the presumed stem cell nature of K15 þ basal cells. Moreover, apoptosis gene array screening of K15 þ microdissected basal cells demonstrated a dominant trend toward the preferential expression of genes associated with protection from apoptosis. Accordingly, genes that regulate apoptotic vulnerability are differentially expressed in basal layer subpopulations distinguishable by K15 expression.
the role of ppARγ in cancer therapy is controversial, with studies showing either pro-tumorigenic... more the role of ppARγ in cancer therapy is controversial, with studies showing either pro-tumorigenic or antineoplastic effects. this debate is very clinically relevant, because ppARγ agonists are used as antidiabetic drugs. Here, we evaluated if the effects of ppARγ on tumorigenesis are determined by the cell type in which ppARγ is activated. Second, we examined if the metabolic changes induced by ppARγ, such as glycolysis and autophagy, play any role in the tumorigenic process. to this end, ppARγ was overexpressed in breast cancer cells or in stromal cells. ppARγ-overexpressing cells were examined with respect to (1) their tumorigenic potential, using xenograft models, and (2) regarding their metabolic features. In xenograft models, we show that when ppARγ is activated in cancer cells, tumor growth is inhibited by 40%. However, when ppARγ is activated in stromal cells, the growth of co-injected breast cancer cells is enhanced by 60%. thus, the effect(s) of ppARγ on tumorigenesis are dependent on the cell compartment in which ppARγ is activated. Mechanistically, stromal cells with activated ppARγ display metabolic features of cancer-associated fibroblasts, with increased autophagy, glycolysis and senescence. Indeed, fibroblasts overexpressing ppARγ show increased expression of autophagic markers, increased numbers of acidic autophagic vacuoles, increased production of L-lactate, cell hypertrophy and mitochondrial dysfunction. In addition, ppARγ fibroblasts show increased expression of CDKs (p16/p21) and β-galactosidase, which are markers of cell cycle arrest and senescence. Finally, ppARγ induces the activation of the two major transcription factors that promote autophagy and glycolysis, i.e., HIF-1α and NFκB, in stromal cells. thus, ppARγ activation in stromal cells results in the formation of a catabolic pro-inflammatory microenvironment that metabolically supports cancer growth. Interestingly, the tumor inhibition observed when ppARγ is expressed in epithelial cancer cells is also associated with increased autophagy, suggesting that activation of an autophagic program has both pro-or antitumorigenic effects depending on the cell compartment in which it occurs. Finally, when ppARγ is expressed in epithelial cancer cells, the suppression of tumor growth is associated with a modest inhibition of angiogenesis. In conclusion, these data support the "two-compartment tumor metabolism" model, which proposes that metabolic coupling exists between catabolic stromal cells and oxidative cancer cells. Cancer cells induce autophagy, glycolysis and senescence in stromal cells. In return, stromal cells generate onco-metabolites and mitochondrial fuels (L-lactate, ketones, glutamine/aminoacids and fatty acids) that are used by cancer cells to enhance their tumorigenic potential. thus, as researchers design new therapies, they must be conscious that cancer is not a cell-autonomous disease, but rather a tumor is an ecosystem of many different cell types, which engage in metabolic symbiosis.
Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different met... more Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (oXpHoS) and the uptake of mitochondrial fuels, as detected via MCt1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/toMM20+/CoX+/MCt1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67−/toMM20−/CoX−/MCt1−); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67−/toMM20−/CoX−/MCt1−). In addition, high oxidative stress (MCt4+) was very specific for cancer tissues. thus, we next evaluated the prognostic value of MCt4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCt4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-pet avidity (p < 0.04). Similarly, oxidative stress (MCt4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCt4 inhibitors should be developed to metabolically target "three-compartment tumor metabolism" in head and neck cancers. It is remarkable that two "non-proliferating" populations of cells (Ki-67−/MCt4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial "fuels" for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial "stem cell" layer is hyper-proliferative (Ki-67+), mitochondrialrich (toMM20+/CoX+) and is metabolically programmed to use mitochondrial fuels (MCt1+), such as ketone bodies and L-lactate. thus, oxidative mitochondrial metabolism (oXpHoS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCt1 and MCt4 inhibitors, to target "metabolic symbiosis."
Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains lar... more Senescent fibroblasts are known to promote tumor growth. However, the exact mechanism remains largely unknown. An important clue comes from recent studies linking autophagy with the onset of senescence. Thus, autophagy and senescence may be part of the same physiological process, known as the autophagy-senescence transition (AST). To test this hypothesis, human fibroblasts immortalized with telomerase (hTeRT-BJ1) were stably transfected with autophagy genes (BNIp3, CTSB or ATG16L1). Their overexpression was sufficient to induce a constitutive autophagic phenotype, with features of mitophagy, mitochondrial dysfunction and a shift toward aerobic glycolysis, resulting in L-lactate and ketone body production. Autophagic fibroblasts also showed features of senescence, with increased p21(WAF1/CIp1), a CDK inhibitor, cellular hypertrophy and increased β-galactosidase activity. Thus, we genetically validated the existence of the autophagy-senescence transition. Importantly, autophagic-senescent fibroblasts promoted tumor growth and metastasis, when co-injected with human breast cancer cells, independently of angiogenesis. Autophagic-senescent fibroblasts stimulated mitochondrial metabolism in adjacent cancer cells, when the two cell types were co-cultured, as visualized by MitoTracker staining. In particular, autophagic ATG16L1 fibroblasts, which produced large amounts of ketone bodies (3-hydroxy-butyrate), had the strongest effects and promoted metastasis by up to 11-fold. Conversely, expression of ATG16L1 in epithelial cancer cells inhibited tumor growth, indicating that the effects of autophagy are compartment-specific. Thus, autophagic-senescent fibroblasts metabolically promote tumor growth and metastasis, by paracrine production of high-energy mitochondrial fuels. Our current studies provide genetic support for the importance of "two-compartment tumor metabolism" in driving tumor growth and metastasis via a simple energy transfer mechanism. Finally, β-galactosidase, a known lysosomal enzyme and biomarker of senescence, was localized to the tumor stroma in human breast cancer tissues, providing in vivo support for our hypothesis. Bioinformatic analysis of genome-wide transcriptional profiles from tumor stroma, isolated from human breast cancers, also validated the onset of an autophagy-senescence transition. Taken together, these studies establish a new functional link between host aging, autophagy, the tumor microenvironment and cancer metabolism.
We and others have recently shown that a loss of caveolin-1 (Cav-1) in stromal cells is a predict... more We and others have recently shown that a loss of caveolin-1 (Cav-1) in stromal cells is a predictor of early tumor recurrence, lymph node metastasis, tamoxifen resistance and poor clinical outcome in human breast cancer patients. 2,3 To investigate the downstream effects of a loss of stromal Cav-1, we isolated bone marrow-derived stromal cells from WT and Cav-1(-/-)-null mice and subjected them to metabolomic and proteomic analyses and genome-wide transcriptional profiling. Interestingly, Cav-1(-/-)
Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. ... more Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCt4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. to address this issue, we cocultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCt4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCt4. We also show that the expression of MCt4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCt4, we see that MCt1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCt4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCt1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCt4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. these data are consistent with the "reverse Warburg effect," which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, "energy transfer" or "metabolic-coupling" between the tumor stroma and epithelial cancer cells "fuels" tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCt inhibitors.
We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast ... more We have previously shown that a loss of stromal Cav-1 is a biomarker of poor prognosis in breast cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy, mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive tGF-β signaling. However, it remains unknown whether hyperactivation of the tGF-β signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. to address these issues, we overexpressed tGF-β ligands and the tGF-β receptor I (tGF-β-RI) in stromal fibroblasts and breast cancer cells. Here, we show that the role of tGF-β in tumorigenesis is compartment-specific, and that tGF-β promotes tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the tumorpromoting effects of tGF-β are independent of the cell type generating tGF-β. thus, stromal-derived tGF-β activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that tGF-β-activated fibroblasts promote the mitochondrial activity of adjacent cancer cells, and in a xenograft model, enhancing the growth of breast cancer cells, independently of angiogenesis. Conversely, activation of the tGF-β pathway in cancer cells does not influence tumor growth, but cancer cell-derived-tGF-β ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced tumor growth. In conclusion, ligand-dependent or cellautonomous activation of the tGF-β pathway in stromal cells induces their metabolic reprogramming, with increased oxidative stress, autophagy/mitophagy and glycolysis, and downregulation of Cav-1. these metabolic alterations can spread among neighboring fibroblasts and greatly sustain the growth of breast cancer cells. our data provide novel insights into the role of the tGF-β pathway in breast tumorigenesis, and establish a clear causative link between the tumor-promoting effects of tGF-β signaling and the metabolic reprogramming of the tumor microenvironment.
enzymes for energy production, via oxidative phosphorylation. During this process (OXPHOS), react... more enzymes for energy production, via oxidative phosphorylation. During this process (OXPHOS), reactive oxygen species (ROS) are generated as by-products of the reduction of molecular oxygen to water. In addition to ROS, the mitochondrial respiratory chain can also produce nitric oxide, which is another free radical F.S. and her laboratory were supported by grants from the Breast Cancer Alliance (BCA) and the American Cancer Society (ACS).
We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In... more We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In this scenario, cancer cells behave as metabolic parasites, by extracting nutrients from normal host cells, such as fibroblasts, via the secretion of hydrogen peroxide as the initial trigger. oxidative stress in the tumor microenvironment then leads to autophagy-driven catabolism, mitochondrial dys-function and aerobic glycolysis. this, in turn, produces high-energy nutrients (such as L-lactate, ketones and glutamine) that drive the anabolic growth of tumor cells, via oxidative mitochondrial metabolism. a logical prediction of this new "parasitic" cancer model is that tumor-associated fibroblasts should show evidence of mitochondrial dys-function (mitophagy and aerobic glycolysis). In contrast, epithelial cancer cells should increase their oxidative mitochondrial capacity. to further test this hypothesis, here we subjected frozen sections from human breast tumors to a staining procedure that only detects functional mitochondria. this method detects the in situ enzymatic activity of cytochrome C oxidase (CoX), also known as Complex IV. Remarkably, cancer cells show an overabundance of CoX activity, while adjacent stromal cells remain essentially negative. adjacent normal ductal epithelial cells also show little or no CoX activity, relative to epithelial cancer cells. thus, oxidative mitochondrial activity is selectively amplified in cancer cells. although CoX activity staining has never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. similar results were obtained with NaDh activity staining, which measures Complex I activity, and succinate dehydrogenase (sDh) activity staining, which measures Complex II activity. CoX and NaDh activities were blocked by electron transport inhibitors, such as Metformin. this has mechanistic and clinical implications for using Metformin as an anti-cancer drug, both for cancer therapy and chemo-prevention. We also immuno-stained human breast cancers for a series of well-established protein biomarkers of metabolism. More specifically, we now show that cancer-associated fibroblasts overexpress markers of autophagy (cathepsin B), mitophagy (BNIp3L) and aerobic glycolysis (MCt4). Conversely, epithelial cancer cells show the overexpression of a mitochondrial membrane marker (toMM20), as well as key components of Complex IV (Mt-Co1) and Complex II (sDh-B). We also validated our observations using a bioinformatics approach with data from >2,000 breast cancer patients, which showed the transcriptional upregulation of mitochondrial oxidative phosphorylation (oXphos) in human breast tumors (p < 10-20), and a specific association with metastasis. therefore, upregulation of oXphos in epithelial tumor cells is a common feature of human breast cancers. In summary, our data provide the first functional in vivo evidence that epithelial cancer cells perform enhanced mitochondrial oxidative phosphorylation, allowing them to produce high amounts of atp. thus, we believe that mitochondria are both the "powerhouse" and "achilles' heel" of cancer cells.
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Papers by Diana Menezes