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A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype

Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, et al.

Carcinogenesis, 2018 05 28;39(6):798-807.
PMID: 29506142 DOI: 10.1093/carcin/bgy032

The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.

Matched MeSH terms: Cancer-Associated Fibroblasts/metabolism*
Single-cell analysis on stromal fibroblasts in the microenvironment of solid tumours

Musa M

Adv Med Sci, 2020 Mar;65(1):163-169.
PMID: 31972467 DOI: 10.1016/j.advms.2019.12.001

Besides malignant cells, the tumour microenvironment consists of various stromal cells such as cancer-associated fibroblasts (CAFs) and myofibroblasts. Accumulation of heterogeneous populations of stromal cells in solid tumours is associated with lower survival rates and cancer recurrence in patients. Certain limitations presented by conventional experimental designs and techniques in cancer research have led to poor understanding of the fundamental basis of cancer niche. Recent developments in single-cell techniques allow more in-depth studies of the tumour microenvironment. Analyses at the single-cell level enables the detection of rare cell types, characterization of intra-tumour cellular heterogeneity and analysis of the lineage output of malignant cells. This subsequently, provides valuable insights on better diagnostic methods and treatment avenues for cancer. This review explores the recent advancements and applications of single-cell technologies in cancer research pertaining to the study of stromal fibroblasts in the microenvironment of solid tumours.

Matched MeSH terms: Cancer-Associated Fibroblasts/metabolism
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: Cancer-Associated Fibroblasts/metabolism*
Stromal podoplanin expression and its clinicopathological role in breast carcinoma

Kumcu E, Unverdi H, Kaymaz E, Oral O, Turkbey D, Hucmenoglu S

Malays J Pathol, 2018 Aug;40(2):137-142.
PMID: 30173230

INTRODUCTION: Breast cancer is still a serious health problem in 21st century and diagnosis, treatment and prognosis of this malignant disease are subject to many research. While cancer research has been focused on tumour cells primarily, recent studies showed that tumour stroma contribute to carcinogenesis as well as tumour cells. Especially fibroblasts adjacent to epithelial tumour cells are not ordinary fibroblasts and play the critical role. Studies showed that these cancer associated fibroblasts (CAFs) have different genetic profile and protein expression. One of the differently expressed molecules recently found is podoplanin. Podoplanin, utilised as a lymphatic endothelial marker, is found to be expressed in CAFs. The aim of this study is to evaluate the relationship between the stromal expression of podoplanin in invasive breast carcinoma and clinicopathological parameters.
MATERIALS & METHODS: Podoplanin expression was evaluated immunohistochemically in 153 breast cancers. Tumours with ≥ 10% distinct cytoplasmic podoplanin staining in CAFs were considered as positive.
RESULTS: In 65.3% of analysed tumours, podoplanin expression was found positive in CAFs. According to our results, podoplanin positive CAFs correlated significantly with tumour size (p= 0.012), tumour grade (p= 0.032) and cerbB2 score (p= 0.032).
DISCUSSION: Our results suggest that podoplanin expression by CAFs could predict poor patient outcome in breast carcinoma.

Matched MeSH terms: Cancer-Associated Fibroblasts/metabolism
Cancer-associated fibroblasts of colorectal cancer and their markers: updates, challenges and translational outlook

Musa M, Ali A

Future Oncol, 2020 Oct;16(29):2329-2344.
PMID: 32687721 DOI: 10.2217/fon-2020-0384

Accumulation of cancer-associated fibroblasts (CAFs) in the tumor microenvironment is associated with poor prognosis and recurrence of colorectal cancer (CRC). Despite their prominent roles in colorectal carcinogenesis, there is a lack of robust and specific markers to classify the heterogeneous and highly complex CAF populations. This has resulted in confusing and misleading definitions of CAFs in cancer niche. Advancements in molecular biology approaches have open doors to reliable CAF marker detection methods in various solid tumors. These discoveries would contribute to more efficient screening, monitoring and targeted therapy of CRC thus potentially will reduce cancer morbidity and mortality rates. This review highlights current scenarios, dilemma, translational potentials of CAF biomarker and future therapeutic applications involving CAF marker identification in CRC.

Matched MeSH terms: Cancer-Associated Fibroblasts/metabolism*
Fulltext Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification

Wu YS, Looi CY, Subramaniam KS, Masamune A, Chung I

Oncotarget, 2016 Jun 14;7(24):36719-36732.
PMID: 27167341 DOI: 10.18632/oncotarget.9165

Pancreatic stellate cells (PSC), a prominent stromal cell, contribute to the progression of pancreatic ductal adenocarcinoma (PDAC). We aim to investigate the mechanisms by which PSC promote cell proliferation in PDAC cell lines, BxPC-3 and AsPC-1. PSC-conditioned media (PSC-CM) induced proliferation of these cells in a dose- and time-dependent manner. Nrf2 protein was upregulated and subsequently, its transcriptional activity was increased with greater DNA binding activity and transcription of target genes. Downregulation of Nrf2 led to suppression of PSC-CM activity in BxPC-3, but not in AsPC-1 cells. However, overexpression of Nrf2 alone resulted in increased cell proliferation in both cell lines, and treatment with PSC-CM further enhanced this effect. Activation of Nrf2 pathway resulted in upregulation of metabolic genes involved in pentose phosphate pathway, glutaminolysis and glutathione biosynthesis. Downregulation and inhibition of glucose-6-phosphate-dehydrogenase with siRNA and chemical approaches reduced PSC-mediated cell proliferation. Among the cytokines present in PSC-CM, stromal-derived factor-1 alpha (SDF-1α) and interleukin-6 (IL-6) activated Nrf2 pathway to induce cell proliferation in both cells, as shown with neutralization antibodies, recombinant proteins and signaling inhibitors. Taken together, SDF-1α and IL-6 secreted from PSC induced PDAC cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification.

Matched MeSH terms: Cancer-Associated Fibroblasts/metabolism
Fulltext Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment

Looi CK, Chung FF, Leong CO, Wong SF, Rosli R, Mai CW

J Exp Clin Cancer Res, 2019 Apr 15;38(1):162.
PMID: 30987642 DOI: 10.1186/s13046-019-1153-8

BACKGROUND: Pancreatic cancer is one of the most lethal type of cancers, with an overall five-year survival rate of less than 5%. It is usually diagnosed at an advanced stage with limited therapeutic options. To date, no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Compared with other cancers, pancreatic cancer exhibits remarkable resistance to conventional therapy and possesses a highly immunosuppressive tumor microenvironment (TME).
MAIN BODY: In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME.
CONCLUSIONS: It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.

Matched MeSH terms: Cancer-Associated Fibroblasts/metabolism
Cancer-associated fibroblasts regulate keratinocyte cell-cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer

Cirillo N, Hassona Y, Celentano A, Lim KP, Manchella S, Parkinson EK, et al.

Carcinogenesis, 2017 01;38(1):76-85.
PMID: 27803052 DOI: 10.1093/carcin/bgw113

The interrelationship between malignant epithelium and the underlying stroma is of fundamental importance in tumour development and progression. In the present study, we used cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), tumours that are characterized by the loss of genes such as TP53 and p16INK4A and with extensive loss of heterozygosity, together with CAFs from their more genetically stable (GS) counterparts that have wild-type TP53 and p16INK4A and minimal loss of heterozygosity (GS-OSCC). Using a systems biology approach to interpret the genome-wide transcriptional profile of the CAFs, we show that transforming growth factor-β (TGF-β) family members not only had biological relevance in silico but also distinguished GU-OSCC-derived CAFs from GS-OSCC CAFs and fibroblasts from normal oral mucosa. In view of the close association between TGF-β family members, we examined the expression of TGF-β1 and TGF-β2 in the different fibroblast subtypes and showed increased levels of active TGF-β1 and TGF-β2 in CAFs from GU-OSCC. CAFs from GU-OSCC, but not GS-OSCC or normal fibroblasts, induced epithelial-mesenchymal transition and down-regulated a broad spectrum of cell adhesion molecules resulting in epithelial dis-cohesion and invasion of target keratinocytes in vitro in a TGF-β-dependent manner. The results demonstrate that the TGF-β family of cytokines secreted by CAFs derived from genotype-specific oral cancer (GU-OSCC) promote, at least in part, the malignant phenotype by weakening intercellular epithelial adhesion.

Matched MeSH terms: Cancer-Associated Fibroblasts/metabolism