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HeatMaps of gene transcripts associated with aging, apoptosis and BRCA1 mutation-positive breast cancer patients. Note that Cav-1-deficient stroma shows the upregulation of aging (73 transcripts), apoptosis (51 transcripts) and BRCA1-mutation associated genes (20 transcripts). See Supplemental Tables 7, 9 and 14.
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Breast cancer progression and metastasis are driven by complex and reciprocal interactions, between epithelial cancer cells and their surrounding stromal microenvironment. We have previously shown that a loss of stromal Cav-1 expression is associated with an increased risk of early tumor recurrence, metastasis and decreased overall survival. To ide...
Contexts in source publication
Context 1
... there was a closer association with ER(-) negative breast cancers, that was identified either by ER IHC or via ESR1 transcriptional analysis (Fig. 10). Furthermore, we also observed an association with an ER(-) gene signature via gene set enrichment analysis (GSEA) (Fig. 7), as well as hereditary breast cancer patients that harbor BRCA1-mutations (Fig. 6). Importantly, these associa- tions were all made with existing gene set data that were derived from whole breast tumors that were not laser-captured to isolate their stroma. This indicates that these stromal signatures can still be used effectively in conjunction with gene profiling data obtained from whole breast ...
Context 2
... that harbor BRCA1/2 muta- tions. 48 Here, we arrived at a similar conclusion. Gene set enrich- ment analysis (GSEA) of the tumor stroma of breast cancer patients with a loss of stromal Cav-1 showed the dramatic upreg- ulation of gene transcripts normally associated with DNA dam- age and repair (Fig. 5) and breast tumors with BRCA1-mutations (Fig. 6). Thus, stromal ROS production, resulting in stromal DNA damage, may be an underestimated driver of tumor pro- gression and metastasis. These findings may also have relevance for guiding the use of DNA damaging agents and/or PARP inhibitors, as potential treatments for breast cancer patients with Cav-1-deficient ...
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Citations
... Witkiewicz et al (41) showed that reduced CAV-1 expression in breast cancer tumor stroma is linked to increased expression of the glycolytic enzymes PKM2 and LDH (41). This phenomenon, called the "reverse Warburg effect," describes how the absence of CAV-1 triggers a metabolic shift from oxidative phosphorylation to glycolysis, creating a microenvironment that promotes the development of the neighboring tumor. ...
... Witkiewicz et al (41) showed that reduced CAV-1 expression in breast cancer tumor stroma is linked to increased expression of the glycolytic enzymes PKM2 and LDH (41). This phenomenon, called the "reverse Warburg effect," describes how the absence of CAV-1 triggers a metabolic shift from oxidative phosphorylation to glycolysis, creating a microenvironment that promotes the development of the neighboring tumor. ...
Background:
Breast cancer (BC) plays a major public health in Egyptian woman. In Upper Egypt, there is an increase in incidence of BC compared to other Egyptian areas. Triple-negative BC, estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-neu-negative, is a high-risk BC that lacks the benefit of specific therapy that targets these proteins. Accurate determination of Caveolin-1(Cav-1), Caveolin-2 (Cav-2) and HER-2/neu status have become of major clinical significance in BC by focusing about its role as a tumor marker for response to different therapies.
Methods:
The present study was performed on 73 female BC patients in the South Egypt Cancer Institute. Blood samples were used for Cav-1, Cav-2, and HER-2/neu genes amplification and expression. In addition, immunohistological analysis of mammaglobin, GATA3, ER, PR, and HER-2/neu was done.
Results:
There was a statistically significant association between Cav-1, 2 and HER-2/neu genes expression and the age of patients (P< 0.001). There are increase in the level of Cav-1, 2 and increase in HER-2/neu mRNA expression in groups treated with chemotherapy and group treated with both chemotherapy and radiotherapy compared to each group baseline level of genes mRNA expression before treatment. On the contrary, the group treated with chemotherapy, radiotherapy and hormonal therapy revealed increase on the level of Cav-1, 2 and HER-2/neu mRNA expression when compared with their baseline for the same patients before treatment.
Conclusions:
Noninvasive molecular biomarkers such as Cav-1 and Cav-2 have been proposed for use in the diagnosis and prognosis for women with BC.
... Witkiewicz et al (41) showed that reduced CAV-1 expression in breast cancer tumor stroma is linked to increased expression of the glycolytic enzymes PKM2 and LDH (41). This phenomenon, called the "reverse Warburg effect," describes how the absence of CAV-1 triggers a metabolic shift from oxidative phosphorylation to glycolysis, creating a microenvironment that promotes the development of the neighboring tumor. ...
... Witkiewicz et al (41) showed that reduced CAV-1 expression in breast cancer tumor stroma is linked to increased expression of the glycolytic enzymes PKM2 and LDH (41). This phenomenon, called the "reverse Warburg effect," describes how the absence of CAV-1 triggers a metabolic shift from oxidative phosphorylation to glycolysis, creating a microenvironment that promotes the development of the neighboring tumor. ...
Background: Breast cancer (BC) plays a major public health in Egyptian woman. In Upper Egypt, there is an increase in incidence of BC compared to other Egyptian areas. Triple-negative BC, estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-neu-negative, is a high-risk BC that lacks the benefit of specific therapy that targets these proteins. Accurate determination of Caveolin-1(Cav-1), Caveolin-2 (Cav-2) and HER-2/neu status have become of major clinical significance in BC by focusing about its role as a tumor marker for response to different therapies. Methods: The present study was performed on 73 female BC patients in the South Egypt Cancer Institute. Blood samples were used for Cav-1, Cav-2, and HER-2/neu genes amplification and expression. In addition, immunohistological analysis of mammaglobin, GATA3, ER, PR, and HER-2/neu was done. Results: There was a statistically significant association between Cav-1, 2 and HER-2/neu genes expression and the age of patients (P< 0.001). There are increase in the level of Cav-1, 2 and increase in HER-2/neu mRNA expression in groups treated with chemotherapy and group treated with both chemotherapy and radiotherapy compared to each group baseline level of genes mRNA expression before treatment. On the contrary, the group treated with chemotherapy, radiotherapy and hormonal therapy revealed increase on the level of Cav-1, 2 and HER-2/neu mRNA expression when compared with their baseline for the same patients before treatment. Conclusions: Noninvasive molecular biomarkers such as Cav-1 and Cav-2 have been proposed for use in the diagnosis and prognosis for women with BC.
... Low CAV1 expression in the stromal fibroblasts is mediated by oxidative stress, which increases the degradation of CAV1 by autophagy [26]. In breast-cancer tumor stroma, CAV1 expression is decreased, which was associated with increased expression of glycolytic enzymes, PKM2 and LDH [112]. This has been termed as the "reverse Warburg effect" indicating that loss of CAV1 drives a switch from oxidative phosphorylation to glycolysis, generating a microenvironment that drives the growth of the adjacent tumor. ...
Simple Summary
Cell membranes contain small invaginations called caveolae. They are a specialized lipid domain and orchestrate cellular signaling events, mechanoprotection, and lipid homeostasis. Formation of the caveolae depends on two classes of proteins, the caveolins and cavins, which form large complexes that allow their self-assembly into caveolae. Loss of either of these two proteins leads to distortion of the caveolae structure and disruption of many physiological processes that affect diseases of the muscle, metabolic states governing lipids, and the glucose balance as well as cancers. In cancers, the expression of caveolins and cavins is heterogenous, and they undergo alterations both in the tumors and the surrounding tumor microenvironment stromal cells. Remarkably, their expression and function has been associated with resistance to many cancer drugs. Here, we summarize the current knowledge of the resistance mechanisms and how this knowledge could be applied into the clinic in future.
Abstract
The discovery of small, “cave-like” invaginations at the plasma membrane, called caveola, has opened up a new and exciting research area in health and diseases revolving around this cellular ultrastructure. Caveolae are rich in cholesterol and orchestrate cellular signaling events. Within caveola, the caveola-associated proteins, caveolins and cavins, are critical components for the formation of these lipid rafts, their dynamics, and cellular pathophysiology. Their alterations underlie human diseases such as lipodystrophy, muscular dystrophy, cardiovascular disease, and diabetes. The expression of caveolins and cavins is modulated in tumors and in tumor stroma, and their alterations are connected with cancer progression and treatment resistance. To date, although substantial breakthroughs in cancer drug development have been made, drug resistance remains a problem leading to treatment failures and challenging translation and bench-to-bedside research. Here, we summarize the current progress in understanding cancer drug resistance in the context of caveola-associated molecules and tumor stroma and discuss how we can potentially design therapeutic avenues to target these molecules in order to overcome treatment resistance.
... MCT1 has a key role in energy transfer by establishing a lactate shuttle-system [36,37]. Tumor cells import and utilize lactate for oxidative energy production (reverse Warburg metabolism), and the presence of these reverse Warburg cells is associated with a more aggressive phenotype and worse prognosis in breast, prostate, endometrial or colorectal cancer [36,[38][39][40][41][42]. Furthermore, high MCT1 expression in tumor cells is associated with reverse Warburg metabolism [43,44], and silencing of MCT1 decreases resistance to chemotherapy in pancreatic adenocarcinoma cells [45]. ...
Simple Summary
Synovial sarcoma (SS) is associated with a high risk of recurrence and poor prognosis, and no biomarker useful in monitoring tumor burden exists. We identified monocarboxylate transporter 1 (MCT1) expressed in extracellular vesicles (EVs) derived from synovial sarcoma as a potential such marker. Circulating levels of MCT1⁺CD9⁺ EVs were significantly correlated with tumor volume in a SS mouse model. Serum levels of MCT1⁺CD9⁺ EVs reflected tumor burden and treatment response in SS patients. Patients with MCT1 expression on the plasma membrane have significantly worse overall survival than those with nuclear expression. Silencing of MCT1 reduced the malignant phenotype including cellular viability, migration, and invasion of SS cells. MCT1 may thus be a promising novel target for liquid biopsies and a novel therapeutic target.
Abstract
The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1⁺CD9⁺ EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1⁺CD9⁺ EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1⁺CD9⁺ EVs and indicates the therapeutic potential of MCT1 in SS.
... Guaita-Esteruelas et al proposed that exogenous FABP4, which is responsive to signals that induce lipolysis, facilitates the uptake of fatty acids into breast cancer cells, playing a key role in tumor progression (53,54). On the other hand, Witkiewicz et al showed that a reduction or loss of stromal caveolin 1 expression is usually associated with increased risk of early tumor recurrence, metastasis and decreased overall survival (55). Our results showed increased FABP4 expression and decreased caveolin 1 in BAs which, taken together with an increased mobility of fatty acids induced by UCP1 activation (56), suggest that BA tissue could promote tumor cell progression. ...
Adipocytes are the main stromal cells in the mammary microenvironment, and crosstalk between adipocytes and breast cancer cells may play a critical and important role in cancer maintenance and progression. Tumor‑induced differentiation to beige/brown adipose tissue is an important contribution to the hypermetabolic state of breast cancer. However, the effect of epithelial cell‑beige adipocyte communication on tumor progression remains unclear. To contribute to the understanding of this phenomenon, we characterized components present in conditioned media (CM) from beige adipocytes (BAs) or white adipocytes (WAs), and evaluated the effects of BA‑ and WA‑CM on both adhesion and migration of tumor (LM3, 4T1 and MC4‑L1) and non‑tumor (NMuMG) mouse mammary epithelial cell lines. Additionally, we analyzed the expression of ObR, CD44, vimentin, MMP‑9, MCT1 and LDH in tumor and non‑tumor mouse mammary epithelial cell lines incubated with BA‑CM, WA‑CM or Ctrol‑CM (control conditioned media). 3T3‑L1 preadipocytes differentiated into beige adipocytes upon PPARγ activation (rosiglitazone) displaying characteristics that morphologically resembled brown/beige adipocytes. Levels of UCP1, CIDEA, GLUT4, leptin, MCT4 and FABP4 were increased, while adiponectin, caveolin 1 and perilipin 1 levels were decreased in BAs with respect to WAs. Tumor cell lines revealed lower cell adhesion and increased cell migration after incubation with BA‑ and WA‑CM vs. Ctrol‑CM. ObR and MMP‑9 in MC4‑L1 cells were significantly increased after incubation with BA‑CM vs. WA‑ and Ctrol‑CM. In addition, MC4‑L1 and LM3 cells significantly increased their migration in the presence of BAs, suggesting that new signals originating from the crosstalk between BAs and tumor cells, could be responsible for this change. Our results indicate that beige adipocytes are able to regulate the behavior of both tumor and non‑tumor mouse mammary epithelial cells, favoring tumor progression.
... Interestingly, in this context, the loss of CAV1 expression in breast cancer tumor-stroma reportedly induces HIF1α activation [28] and the loss of CAV1 in stromal cells leads to a glycolytic and catabolic phenotype through HIF1α stabilization, favoring synergy with oxidative breast cancer cells [29]. Moreover, the analysis of tissue samples from CAV1 knockout mice revealed an increase in HIF1α target gene expression [30]. ...
... Previous studies analyzing CAV1 knockout mice and stroma from breast cancer patients revealed that increased HIF1α target gene expression correlated with reduced CAV1 levels [28,30,63]. In gastric cancer cells, hypoxia (1% O 2 )-enhanced HIF1α stabilization coincides with the downregulation of CAV1 expression and epithelial-mesenchymal transition [64]. ...
Caveolin-1 (CAV1) is a well-established nitric oxide synthase inhibitor, whose function as a tumor suppressor is favored by, but not entirely dependent on, the presence of E-cadherin. Tumors are frequently hypoxic and the activation of the hypoxia-inducible factor-1α (HIF1α) promotes tumor growth. HIF1α is regulated by several post-translational modifications, including S-nitrosylation. Here, we evaluate the mechanisms underlying tumor suppression by CAV1 in cancer cells lacking E-cadherin in hypoxia. Our main findings are that CAV1 reduced HIF activity and Vascular Endothelial Growth Factor expression in vitro and in vivo. This effect was neither due to reduced HIF1α protein stability or reduced nuclear translocation. Instead, HIF1α S-nitrosylation observed in hypoxia was diminished by the presence of CAV1, and nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) reduced HIF1α transcriptional activity in cells to the same extent as observed upon CAV1 expression. Additionally, arginase inhibition by (S)-(2-Boronoethyl)-L-cysteine (BEC) partially rescued cells from the CAV1-mediated suppression of HIF1α transcriptional activity. In vivo, CAV1-mediated tumor suppression was dependent on NOS activity. In summary, CAV1-dependent tumor suppression in the absence of E-cadherin is linked to reduced HIF1α transcriptional activity via diminished NOS-mediated HIF1α S-nitrosylation.
... There is increasing attention to a specific role of Cav-1 in the tumor-associated stroma. A loss of Cav-1 expression in the breast tumor stroma correlated with an increased risk for early recurrence, metastatic progression, and decreased survival in patients [11][12][13]. A retrospective patient cohort study revealed that nearly 90% of estrogen receptor (ER) positive DCIS patients that had recurred to IBC showed diminished or completely absent Cav-1 expression in their tumor stroma [14]. ...
Ductal carcinoma in situ (DCIS) is one of the earliest stages of breast cancer (BCa). The mechanisms by which DCIS lesions progress to an invasive state while others remain indolent are yet to be fully characterized and both diagnosis and treatment of this pre-invasive disease could benefit from better understanding the pathways involved. While a decreased expression of Caveolin-1 (Cav-1) in the tumor microenvironment of patients with DCIS breast cancer was linked to progression to invasive breast cancer (IBC), the downstream effector(s) contributing to this process remain elusive. The current report shows elevated expression of Signal Transducer and Activator of Transcription 5a (STAT5a) within the DCIS-like lesions in Cav-1 KO mice following estrogen treatment and inhibition of STAT5a expression prevented the formation of these mammary lesions. In addition, STAT5a overexpression in a human DCIS cell line (MCF10DCIS.com) promoted their invasion, a process accelerated by estrogen treatment and associated with increased levels of the matrix metalloproteinase-9 (MMP-9) precursor. In sum, our results demonstrate a novel regulatory axis (Cav-1♦STAT5a♦MMP-9) in DCIS that is fully activated by the presence of estrogen. Our studies suggest to further study phosphorylated STAT5a (Y694) as a potential biomarker to guide and predict outcome of DCIS patient population.
... Mechanistically, HIF1-alpha and NF-κB signaling are the master pathways that drive oxidative stress, then induce autophagy and senescence in CAFs (59)(60)(61)(62)(63). Moreover, caveolin-1 (Cav-1) and monocarboxylate transporter 4 (MCT4) are new biomarkers of this CAF phenotype. ...
Metastasis is regarded as the most important cause of cancer-related deaths around the world. During the complicated metastatic cascade, altered mitochondrial metabolism adapts to serve distinct conditions and microenvironments. In this review, we discuss how cells regulate their mitochondria metabolism to adapt to environmental cues during the metastasis, as well as how cancer cells and their tumor micro-environment (TME) are metabolically coupled during the metastatic cascade. We place a strong emphasis on how mitochondrial proline metabolism and extracellular matrix (ECM) are coupled.
... In this fashion, metabolic symbiosis and energy transfer is maintained between stromal and tumor cells or between tumor cells themselves [17][18][19], a modality termed "reverse Warburg" [20]. Recent studies revealed that reverse Warburg conditions are implicated in the progression and poor outcome of malignancies, e.g., breast, prostate, endometrial or colorectal cancer [21][22][23][24][25][26]. The lactate/proton symporter monocarboxylate transporter-1 (MCT1) and -4 (MCT4) have a key role in the energy transfer by establishing a lactate shuttle-system. ...
Metabolite exchange between stromal and tumor cells or among tumor cells themselves accompanies metabolic reprogramming in cancer including pancreatic adenocarcinoma (PDAC). Some tumor cells import and utilize lactate for oxidative energy production (reverse Warburg-metabolism) and the presence of these “reverse Warburg“ cells associates with a more aggressive phenotype and worse prognosis, though the underlying mechanisms are poorly understood. We now show that PDAC cells (BxPc3, A818-6, T3M4) expressing the lactate-importer monocarboxylate transporter-1 (MCT1) are protected by lactate against gemcitabine-induced apoptosis in a MCT1-dependent fashion, contrary to MCT1-negative PDAC cells (Panc1, Capan2). Moreover, lactate administration under glucose starvation, resembling reverse Warburg co a phenotype of BxPc3 and T3M4 cells that confers greater potential of clonal growth upon re-exposure to glucose, along with drug resistance and elevated expression of the stemness marker Nestin and reprogramming factors (Oct4, KLF4, Nanog). These lactate dependent effects on stemness properties are abrogated by the MCT1/lactate-uptake inhibitor 7ACC2 or MCT1 knock-down. Furthermore, the clinical relevance of these observations was supported by detecting co-expression of MCT1 and reprogramming factors in human PDAC tissues. In conclusion, the MCT1-dependent import of lactate supplies “reverse Warburg “PDAC cells with an efficient driver of metabostemness. This condition may essentially contribute to malignant traits including therapy resistance.
... Interestingly, we found NRF1 binding sites to be enriched in upregulated gene promoters as well as proximal peaks with increased H3K9ac. NRF1 (nuclear respiratory factor 1) is required for expression of key metabolic genes regulating cellular growth including several nuclear-encoded mitochondrial genes [38]. Given the role of NRF1 in regulating metabolic genes, we tested whether NRF1 binding at its target sites was enhanced after insulin treatment. ...
Background:
Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC.
Results:
MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells.
Conclusions:
These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.
