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Fulltext A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts

Kabir TD, Leigh RJ, Tasena H, Mellone M, Coletta RD, Parkinson EK, et al.

Aging (Albany NY), 2016 08;8(8):1608-35.
PMID: 27385366 DOI: 10.18632/aging.100987

Senescent cancer-associated fibroblasts (CAF) develop a senescence-associated secretory phenotype (SASP) that is believed to contribute to cancer progression. The mechanisms underlying SASP development are, however, poorly understood. Here we examined the functional role of microRNA in the development of the SASP in normal fibroblasts and CAF. We identified a microRNA, miR-335, up-regulated in the senescent normal fibroblasts and CAF and able to modulate the secretion of SASP factors and induce cancer cell motility in co-cultures, at least in part by suppressing the expression of phosphatase and tensin homologue (PTEN). Additionally, elevated levels of cyclo-oxygenase 2 (PTGS2; COX-2) and prostaglandin E2 (PGE2) secretion were observed in senescent fibroblasts, and inhibition of COX-2 by celecoxib reduced the expression of miR-335, restored PTEN expression and decreased the pro-tumourigenic effects of the SASP. Collectively these data demonstrate the existence of a novel miRNA/PTEN-regulated pathway modulating the inflammasome in senescent fibroblasts.

Matched MeSH terms: Cell Aging/physiology*
Fulltext Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis

Mellone M, Hanley CJ, Thirdborough S, Mellows T, Garcia E, Woo J, et al.

Aging (Albany NY), 2016 12 15;9(1):114-132.
PMID: 27992856 DOI: 10.18632/aging.101127

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.

Matched MeSH terms: Cell Aging/physiology*
Fulltext Non-infarcted myocardium bears the weight in CVD

Zhou H, Zainal H, Puntmann VO

Aging (Albany NY), 2019 03 25;11(6):1609-1610.
PMID: 30908271 DOI: 10.18632/aging.101890
Fulltext Efficacy of zinc carnosine in the treatment of colorectal cancer and its potential in combination with immunotherapy in vivo

Tang W, Liu H, Li X, Ooi TC, Rajab NF, Cao H, et al.

Aging (Albany NY), 2022 Nov 14;14(21):8688-8699.
PMID: 36375474 DOI: 10.18632/aging.204380

BACKGROUND: A complex of Zn and carnosine, called Zinc-L-carnosine (ZnC), enjoys a wide application as part of a Zn supplement therapeutic method as well as in treating peptic ulcers. However, researches fail to confirm the biological functions possessed by ZnC as well as tumor immune microenvironment in colorectal cancer (CRC).
METHODS: Cell counting kit 8(CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell and wound healing assays were conducted to study the influence of ZnC in the proliferating, invading and migrating processes of CRC cell lines (HCT116, LOVO) in vitro. The antitumor activity ZnC as well as its effects on tumor immune microenvironment were then assessed using CRC subcutaneous tumors in the C57BL/6 mouse model.
RESULTS: According to CCK8, EdU, transwell and wound healing assays, ZnC inhibited CRC cell lines in terms of proliferation, invasion and migration. ZnC could inhibit miR-570 for up-regulating PD-L1 expression. In vivo experiments showed that gavage (100 mg/kg, once every day) of ZnC inhibited the tumor growth of CRC, and the combination of ZnC and anti-PD1 therapy significantly improved the efficacy exhibited by anti-PD1 in treating CRC. In addition, mass cytometry results showed that immunosuppressive cells including regulatory T cells (tregs), bone marrow-derived suppressor cells (MDSC), and M2 macrophages decreased whereas CD8+ T cells elevated after adding ZnC.
CONCLUSIONS: The present study reveals that ZnC slows the progression of CRC by inhibiting CRC cells in terms of proliferation, invasion and migration, meanwhile up-regulating PD-L1 expression via inhibiting miR-570. The ZnC-anti-PD1 co-treatment assists in synergically increasing anti-tumor efficacy in CRC therapy.
Fulltext It's the holes that matter

Cogger VC, Mohamad M, Le Couteur DG

Aging (Albany NY), 2017 11 15;9(11):2237-2238.
PMID: 29140795 DOI: 10.18632/aging.101330
Fulltext Tryptophan metabolism-related gene expression patterns: unveiling prognostic insights and immune landscapes in uveal melanoma

Wang J, Zhao T, Li B, Wei W

Aging (Albany NY), 2023 Oct 13;15(20):11201-11216.
PMID: 37844995 DOI: 10.18632/aging.205122

Uveal melanoma (UVM) remains the leading intraocular malignancy in adults, with a poor prognosis for those with metastatic disease. Tryptophan metabolism plays a pivotal role in influencing cancerous properties and modifying the tumor's immune microenvironment. In this study, we explore the relationship between tryptophan metabolism-related gene (TRMG) expression and the various features of UVM, including prognosis and tumor microenvironment. Our analysis included 143 patient samples sourced from public databases. Using K-means clustering, we categorized UVM patients into two distinct clusters. Further, we developed a prognostic model based on five essential genes, effectively distinguishing between low-risk and high-risk patients. This distinction underscores the importance of TRMGs in UVM prognostication. Combining TRMG data with gender to create nomograms demonstrated exceptional accuracy in predicting UVM patient outcomes. Moreover, our analysis reveals correlations between risk assessments and immune cell infiltrations. Notably, the low-risk group displayed a heightened potential response to immune checkpoint inhibitors. In conclusion, our findings underscore the dynamic relationship between TRMG expression and various UVM characteristics, presenting a novel prognostic framework centered on TRMGs. The deep connection between TRMGs and UVM's tumor immune microenvironment emphasizes the crucial role of tryptophan metabolism in shaping the immune landscape. Such understanding paves the way for designing targeted immunotherapy strategies for UVM patients.