Landscape of cancer-associated fibroblasts identifies the secreted biglycan as a protumor and immunosuppressive factor in triple-negative breast cancer

Zheng, Shaoquan; Zou, Yutian; Tang, Yuhui; Yang, Anli; Liang, Jie; Wu, Linyu; Tian, Wenwen; Xiao, Weikai; Xie, Xinhua; Yang, Lu; Xie, Jun; Wei-dong, Wang; Xie, Xiaoming

doi:10.1080/2162402x.2021.2020984

Cited by 60 publications

(57 citation statements)

References 72 publications

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“…Another important CAF subpopulation is iCAFs with a low αSMA expression and high cytokine production as well as secretion [ 242 ], found in breast cancer and in pancreas ductal adenocarcinoma (PDAC) [ 240 , 253 ]. This extraordinary secretory activity is related to a high gene expression of important signaling regulators, such as PDGFRα , dermatopontin ( DPT ), C-type lectin domain family 3 member B ( CLEC3B ), collagen type XIV alpha 1 chain ( COL14A1 ), lymphocyte antigen 6c1 ( Ly6c1 ), hyaluronan synthase 1 ( HAS1 ), HAS2 , IL6 , IL8 , IL11 , CXCL1 , CXCL2 , and CCL2 [ 240 , 253 ].…”

Section: Mutual Interaction Between Ascs/mscs and Breast Cancer Cellsmentioning

confidence: 99%

Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer

Ritter

Kreis

Hoock

et al. 2022

Cancers

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Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell–cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial–mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment.

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Section: Mutual Interaction Between Ascs/mscs and Breast Cancer Cellsmentioning

confidence: 99%

Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer

Ritter

Kreis

Hoock

et al. 2022

Cancers

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“…In CD31‐negative cells, CD45‐negative cells but not CD45‐positive cells exhibited biglycan expression (Figure S1 E,F), suggesting some stromal cells, such as fibroblasts, express biglycan, which is consistent with previous reports. 42 , 43 We isolated TECs from OS‐RC‐2 tumor tissues (OS‐RC‐2‐EC) as described previously. 10 , 33 Compared with normal ECs derived from skin tissues (Skin‐EC) or kidney tissues (Kidney‐EC), OS‐RC‐2‐ECs showed high biglycan expression (Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell‐specific liposomal siRNA delivery system

et al. 2022

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Tumor blood vessels play important roles in tumor progression and metastasis. Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. We previously reported that biglycan, a small leucine‐rich proteoglycan, is highly expressed in TECs. TECs utilize biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC‐derived biglycan stimulates tumor cell migration in a paracrine manner leading to tumor cell intravasation and metastasis. In this study, we explored the therapeutic effect of biglycan inhibition in the TECs of renal cell carcinoma using an in vivo siRNA delivery system known as a multifunctional envelope‐type nanodevice (MEND), which contains a unique pH‐sensitive cationic lipid. To specifically deliver MEND into TECs, we incorporated cyclo(Arg–Gly–Asp–D–Phe–Lys) (cRGD) into MEND because αVβ3 integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD‐MEND‐encapsulating siRNA against biglycan. First, we confirmed that MEND was delivered into OS‐RC‐2 tumor‐derived TECs and induced in vitro RNAi‐mediated gene silencing. MEND was then injected intravenously into OS‐RC‐2 tumor‐bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT‐PCR indicated that biglycan was knocked down by biglycan siRNA‐containing MEND. Finally, we analyzed the therapeutic effect of biglycan silencing by MEND in TECs. Tumor growth was inhibited by biglycan siRNA‐containing MEND. Tumor microenvironmental factors such as fibrosis were also normalized using biglycan inhibition in TECs. Biglycan in TECs can be a novel target for cancer treatment.

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“…Recent studies have identified several CAF subclusters with specific signatures and different response to therapies, therefore, internal heterogeneity in CAF subpopulations represents a new challenge in medicine [ 12 ]. In this light, novel technologies such as single-cell sequencing and mass spectrometry have been developed to study single-cell expression profiles and identify new biomarkers for cancer since CAF-derived proteins represent the main actors in intercellular crosstalk [ 13 , 14 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

Mantovani

Caraglia

Jung

et al. 2022

Cancers

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Background: Stromal components surrounding epithelial cancer cells seem to play a pivotal role during epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastases. To identify the molecular mechanisms underlying tumor–stroma interactions may yield novel therapeutic targets for prostate cancer. Methods: Gene expression profile of prostate-cancer associated fibroblast (PCAF) and prostate non-cancer associated fibroblast (PNAF) cells isolated from radical prostatectomy was performed by Illumina, analyzed, and further processed by Ingenuity®: IPA® software. qRT-PCR was performed on an independent set of 17 PCAF, 12 PNAF, and 12 fibroblast cell lines derived from patients with benign prostatic hyperplasia (BPHF). Results: Using microarray analysis, we found six upregulated genes and two downregulated genes in PCAFs compared to PNAFs. To validate microarray results, we performed qRT-PCR for the most significantly regulated genes involved in the modulation of proliferation and androgen resistance on an independent set of PNAF, PCAF, and BHPF samples. We confirmed the increased expression of SCARB1, MAPK3K1, and TGF-β as well as the decreased expression of S100A10 in PCAFs compared to PNAFs and BPHFs. Conclusions: These results provide strong evidence that the observed changes in the gene expression profile of PCAFs can contribute to functional alteration of adjacent prostate cancer cells.

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Landscape of cancer-associated fibroblasts identifies the secreted biglycan as a protumor and immunosuppressive factor in triple-negative breast cancer

Cited by 60 publications

References 72 publications

Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer

Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer

Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell‐specific liposomal siRNA delivery system

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

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