Human Skin Keloid Fibroblasts Display Bioenergetics of Cancer Cells

Vincent, Annette S.; Phan, Than T.; Mukhopadhyay, Anandaroop; Lim, Hwee Ying; Halliwell, Barry; Wong, Kim Ping

doi:10.1038/sj.jid.5701107

Cited by 136 publications

(104 citation statements)

References 49 publications

(49 reference statements)

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“…36,37 In accordance with this notion, keloid fibroblasts (derived from non-tumorous "scarred skin") show many of the same characteristics as Cav-1 deficient tumor stroma, with activation of HIF1-a and NFκB, as well as a shift towards aerobic glycolysis. 27,38,39 Thus, there may be a mechanistic connection between loss of Cav-1 as a driver of tissue fibrosis, tumor progression and metastasis. 40 Consistent with this notion, a fibrotic focus in breast cancers is thought to be a surrogate marker for hypoxia.…”

Section: Discussionmentioning

confidence: 98%

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Witkiewicz¹,

Kline²,

Queenan³

et al. 2011

Cell Cycle

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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 identify and characterize the signaling pathways that are activated in Cav-1 negative tumor stroma, we performed gene expression profiling using laser microdissected breast cancer-associated stroma. Tumor stroma was laser capture microdissected from 4 cases showing high stromal Cav-1 expression and 7 cases with loss of stromal Cav-1. Briefly, we identified 238 gene transcripts that were upregulated and 232 gene transcripts that were downregulated in the stroma of tumors showing a loss of Cav-1 expression (p ≤ 0.01 and fold-change ≥ 1.5). Gene set enrichment analysis (GSEA) revealed "stemness," inflammation, DNA damage, aging, oxidative stress, hypoxia, autophagy and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1. Our findings are consistent with the recently proposed "Reverse Warburg Effect" and the "Autophagic Tumor Stroma Model of Cancer Metabolism." In these two complementary models, cancer cells induce oxidative stress in adjacent stromal cells, which then forces these stromal fibroblasts to undergo autophagy/mitophagy and aerobic glycolysis. This, in turn, produces recycled nutrients (lactate, ketones and glutamine) to feed anabolic cancer cells, which are undergoing oxidative mitochondrial metabolism. Our results are also consistent with previous biomarker studies showing that the increased expression of known autophagy markers (such as ATG16L and the cathepsins) in the tumor stroma is specifically associated with metastatic tumor progression and/or poor clinical outcome.

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Section: Discussionmentioning

confidence: 98%

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Witkiewicz¹,

Kline²,

Queenan³

et al. 2011

Cell Cycle

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“…In contrast, A549 and H1299 cells shifted their metabolism to OXPHOS in response to CAF stimulation. Although the occurrence of the Warburg effect in cancer cells was first proposed by Otto H. Warburg in the early 1920s [8], in 2008, Vincent et al demonstrated that skin myofibroblasts experience aerobic glycolysis exactly like cancer cells [48]. Furthermore, Lisanti et al revealed that caveolin-1-deficient CAFs show the upregulation of both myofibroblast markers and glycolytic enzymes under normoxic conditions and this was associated with the recurrence, metastasis, and poor outcome of human breast cancer [9].…”

Section: Discussionmentioning

confidence: 99%

Cancer-Associated Fibroblasts Accelerate Malignant Progression of Non-Small Cell Lung Cancer via Connexin 43-Formed Unidirectional Gap Junctional Intercellular Communication

Luo

Mao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Gap junctions, which are assembled by connexins, can directly connect the cytoplasm of adjacent cells and enable gap junctional intercellular communication (GJIC) as well as metabolic coupling between neighboring cells. Here, we investigated the role of connexin 43 (Cx43) and its derived GJIC in the interplay between non-small cell lung cancer (NSCLC) cells and cancer-associated fibroblasts (CAFs). Methods: CAFs and NSCLC cells were co-cultured with direct contact and separated using flow cytometry. Glucose uptake, lactate production, and the expression and activity of PKM-2 and LDH-A in sorted CAFs were measured by a colorimetric assay, western blotting, and enzyme-linked immunosorbent assay (ELISA). Meanwhile, E-cadherin and N-cadherin expression and the migration and invasion of sorted NSCLC cells were detected by western blotting, wound width, and Transwell assays. Pyruvate, acetyl-CoA, and citric acid levels, ATP levels, and LDH-B and α-KG activity in sorted NSCLC cells were determined by a colorimetric or fluorometric assay and ELISA, respectively. Functional GJIC between cells and the subcellular location of connexins were detected by a “Parachute” assay and immunofluorescence. Levels of α-SMA, Cx43, and LDH-B in tissue from patients with NSCLC were determined by immunohistochemistry. Results: Cx43 accumulated in the plasma membrane, which favored the assembly of asymmetric unidirectional GJIC from CAFs to NSCLC cells. CAFs underwent increased aerobic glycolysis and promoted the epithelial-mesenchymal transition, migration, and invasion of NSCLC cells. In contrast, NSCLC cells experienced enhanced oxidative phosphorylation upon CAF stimulation, with an increase in ATP generation and thereby activation of the PI3K/Akt and MAPK/ERK pathways. Metabolic coupling between CAFs and NSCLC cells was under the strict control of Cx43-formed unidirectional GJIC. Patients with high tri-expression of α-SMA, Cx43, and LDH-B had the shortest overall survival and relapse-free survival compared with those with individual overexpression or high bi-expression. Conclusion: Cx43-formed unidirectional GJIC plays a critical role in mediating close metabolic cooperation between CAFs and NSCLC cells to support the malignant progression of NSCLC.

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“…Nevertheless, in 2008, Vincent et al demonstrated that human skin keloid fibroblasts display similar bioenergetic changes as cancer cells in generating ATP mainly from glycolysis. The hypoxic microenvironment is a common fact in solid tumors and keloids, which may be the explanation for this thermodynamic phenomenon [4]. In line with these findings, Pavlides and col suggested, in 2009, a novel hypothesis for understanding the Warburg effect in tumors [5]: they proposed that epithelial cancer cells induce the Warburg effect in neighboring stromal fibroblasts.…”

Section: Introductionmentioning

confidence: 93%

Autophagy, Warburg, and Warburg Reverse Effects in Human Cancer

González

Álvarez

Ropolo

et al. 2014

BioMed Research International

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Autophagy is a highly regulated-cell pathway for degrading long-lived proteins as well as for clearing cytoplasmic organelles. Autophagy is a key contributor to cellular homeostasis and metabolism. Warburg hypothesized that cancer growth is frequently associated with a deviation of a set of energy generation mechanisms to a nonoxidative breakdown of glucose. This cellular phenomenon seems to rely on a respiratory impairment, linked to mitochondrial dysfunction. This mitochondrial dysfunction results in a switch to anaerobic glycolysis. It has been recently suggested that epithelial cancer cells may induce the Warburg effect in neighboring stromal fibroblasts in which autophagy was activated. These series of observations drove to the proposal of a putative reverse Warburg effect of pathophysiological relevance for, at least, some tumor phenotypes. In this review we introduce the autophagy process and its regulation and its selective pathways and role in cancer cell metabolism. We define and describe the Warburg effect and the newly suggested “reverse” hypothesis. We also discuss the potential value of modulating autophagy with several pharmacological agents able to modify the Warburg effect. The association of the Warburg effect in cancer and stromal cells to tumor-related autophagy may be of relevance for further development of experimental therapeutics as well as for cancer prevention.

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Human Skin Keloid Fibroblasts Display Bioenergetics of Cancer Cells

Cited by 136 publications

References 49 publications

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Cancer-Associated Fibroblasts Accelerate Malignant Progression of Non-Small Cell Lung Cancer via Connexin 43-Formed Unidirectional Gap Junctional Intercellular Communication

Autophagy, Warburg, and Warburg Reverse Effects in Human Cancer

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