Regulation of Tumor Metabolism and Extracellular Acidosis by the TIMP-10–CD63 Axis in Breast Carcinoma

Najy, Abdo J.; Jung, Young-Suk; Kim, Seongho; Fridman, Rafael; Kim, Hyeong‐Reh C.

doi:10.3390/cells10102721

Cited by 6 publications

(7 citation statements)

References 70 publications

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“…We additionally tested the PMA and siTIMP1 effects on two other membrane proteins, CD44 and carbon anhydrase IX (CAIX). CD44 is another binding partner of TIMP-1 [ 36 ], and CAIX is a downstream target of TIMP-1 and CD63 [ 37 ]. PMA increased CD44 expression, whereas it instead decreased the expression of CAIX ( Figure 1 D).…”

Section: Resultsmentioning

confidence: 99%

“…The TIMP-1 effect on the expression of CAIX, a regulator of cellular pH [ 47 ], was of interest, since TIMP-1 in concert with CD63 was found to upregulate CAIX expression in triple-negative MCF10AneoT and MCF10CA1h BC cells, thereby inducing extracellular acidosis [ 37 ]. Here, we show that, contrary to these previous results, TIMP-1 instead downregulated CAIX plasma membrane abundance in ERα-positive AnD5 cells.…”

Section: Discussionmentioning

confidence: 99%

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A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells

Dittmer¹,

Dittmer²

2022

Cancers

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TIMP-1 is one of the many factors that CAFs have been shown to secret. TIMP-1 can act in a tumor-supportive or tumor-suppressive manner. The purpose of this study was to elucidate the role of CAF-secreted TIMP-1 for the effects of CAFs on breast cancer cell behavior. Breast cancer cells were exposed to conditioned medium collected from TIMP-1-secreting CAFs (CAF-CM), and the specific effects of TIMP-1 on protein expression, migration and growth were examined using TIMP-1-specifc siRNA (siTIMP1), recombinant TIMP-1 protein (rhTIMP-1) and TIMP-1 level-rising phorbol ester. We observed that TIMP-1 increased the expression of its binding partner CD63 and induced STAT3 and ERK1/2 activation by cooperating with CD63 and integrin β1. Since TIMP-1 expression was found to be dependent on STAT3, TIMP-1 activated its own expression, resulting in a TIMP-1/CD63/integrin β1/STAT3 feedback loop. IL-6, a classical STAT3 activator, further fueled this loop. Knock-down of each component of the feedback loop prevented the CAF-induced increase in migratory activity and inhibited cellular growth in adherent cultures in the presence and absence of the anti-estrogen fulvestrant. These data show that TIMP-1/CD63/integrin β1/STAT3 plays a role in the effects of CAFs on breast cancer cell behavior.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells

Dittmer¹,

Dittmer²

2022

Cancers

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“…This leads to survival signals by the activation of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK) [ 14 , 15 ]. Further, this TIMP-1-CD63 (LAMP3) signaling axis has been identified as playing a role in tumor metabolism of breast cancer cells by downstream upregulating aerobic glycolysis through carbonic anhydrase IX (CAIX) and thereby extending cell survival [ 26 ]. Creating this metastatic niche could be a factor leading to the observed overall decrease in PFS and OS in patients with high serum TIMP-1 concentration.…”

Section: Discussionmentioning

confidence: 99%

Comparing TIMP-1 and Hsp70 in Blood and Saliva as Potential Prognostic Markers in HNSCC

et al. 2022

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(1) Background: Currently, there is no clinically used liquid biomarker in head and neck squamous cell carcinoma (HNSCC) patients. One reason could be the limited shedding of tumor material in early disease stages. Molecular diagnostics assessing both blood and especially saliva could potentially improve the accuracy of biomarkers. In this prospective study, two markers, tissue inhibitor of metalloprotease-1 (TIMP-1) and heat shock protein 70 (Hsp70), were analyzed in HNSCC patients. The purpose of the study was to evaluate differences between saliva and serum as sample material. Further, their prognostic and predictive value and usefulness for early detection was assessed. (2) Methods: A total of 73 HNSCC patients were prospectively monitored by collecting blood and saliva before, during, and after therapy, as well as in the follow-up period between 2018 and 2021. In total, 212 serum and 194 saliva samples were collected. A control group consisting of 40 subjects (15 patients with local infections in the head and neck area and 25 without infections) were examined as well. The collected samples were evaluated for the two proteins by using an enzyme-linked immunosorbent assay (ELISA). (3) RESULTS: The TIMP-1 concentration correlated significantly in blood and saliva, whereas the Hsp70 concentration did not. Saliva TIMP-1 was significantly higher in tumor patients compared to the control group (p = 0.013). High pretreatment TIMP-1 saliva levels were associated with significantly poorer disease-free survival (DFS) (p = 0.02). A high saliva TIMP-1/Hsp70 ratio was significantly associated with poorer DFS (HR: 1.4; 95% CI: 1.04–1.88; p = 0.026) and a high TIMP-1 serum concentration was significantly associated with poorer PFS (HR: 1.9; 95% CI: 1.2, 2.8; p = 0.003) and poorer overall survival (OS) (HR: 2.9; 95% CI: 1.4, 5.9; p = 0.003) in the Cox proportional hazards model. The saliva TIMP-1 to Hsp70 ratio was significantly higher at the time of recurrence (p = 0.015). Conclusion: TIMP-1 in serum is a promising prognostic marker for HNSCC. Saliva TIMP-1 and the saliva TIMP-1 to Hsp70 ratio provides additional information on the disease-free survival.

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“…Although some carbohydratemetabolizing enzymes (such as HK2, ENO3 and PKM2) delivered via sEVs are known to remodel the TME, given the opposing functions of glycolytic and mitochondrial metabolic enzymes in the Warburg effect, it remains to be ascertained whether these enzymes exert different functions when sorted into sEVs and in the recipient cells. In addition, since tetraspanins may potentially regulate nutrient metabolism in tumor cells, their use as a biomarker of sEV protein cargo also needs to be considered (Wang et al, 2019;Najy et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Small extracellular vesicles in metabolic remodeling of tumor cells: Cargos and translational application

2022

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Warburg effect is characterized by excessive consumption of glucose by the tumor cells under both aerobic and hypoxic conditions. This metabolic reprogramming allows the tumor cells to adapt to the unique microenvironment and proliferate rapidly, and also promotes tumor metastasis and therapy resistance. Metabolic reprogramming of tumor cells is driven by the aberrant expression and activity of metabolic enzymes, which results in the accumulation of oncometabolites, and the hyperactivation of intracellular growth signals. Recent studies suggest that tumor-associated metabolic remodeling also depends on intercellular communication within the tumor microenvironment (TME). Small extracellular vesicles (sEVs), also known as exosomes, are smaller than 200 nm in diameter and are formed by the fusion of multivesicular bodies with the plasma membrane. The sEVs are instrumental in transporting cargoes such as proteins, nucleic acids or metabolites between the tumor, stromal and immune cells of the TME, and are thus involved in reprogramming the glucose metabolism of recipient cells. In this review, we have summarized the biogenesis and functions of sEVs and metabolic cargos, and the mechanisms through they drive the Warburg effect. Furthermore, the potential applications of targeting sEV-mediated metabolic pathways in tumor liquid biopsy, imaging diagnosis and drug development have also been discussed.

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Regulation of Tumor Metabolism and Extracellular Acidosis by the TIMP-10–CD63 Axis in Breast Carcinoma

Cited by 6 publications

References 70 publications

A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells

A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells

Comparing TIMP-1 and Hsp70 in Blood and Saliva as Potential Prognostic Markers in HNSCC

Small extracellular vesicles in metabolic remodeling of tumor cells: Cargos and translational application

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