Cancer-associated fibroblasts: Origin, function, imaging, and therapeutic targeting

Rimal, Rahul; Desai, Prachi; Daware, Rasika; Hosseinnejad, Aisa; Prakash, Jai; Lammers, Twan; Singh, Smriti

doi:10.1016/j.addr.2022.114504

Cited by 56 publications

(39 citation statements)

References 379 publications

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“…Our study supported the previous conclusions that CAFs could promote the stemness and malignant progression of HCC. Recent studies also reported that CAFs sometimes played the tumor-suppressing function [ 7 ]. Heterogeneity may be an important reason for CAFs to play different roles in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Adaptive changes in the TME are mainly driven by the activation of cancer-associated fibroblasts (CAFs) [ 6 ]. As the predominant stromal cells in the TME, CAFs can reprogram the TME and promote cancer progression by inducing angiogenesis, changing the matrix stiffness, regulating the immune cell response, and secreting exosomes, cytokines and secreted proteins [ 7 , 8 ]. CAFs are associated with the poor prognosis of many kinds of tumors; thus, they have become potential targets for tumor treatment.…”

Section: Introductionmentioning

confidence: 99%

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The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma

et al. 2023

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Background Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment (TME), play crucial roles in tumor stemness. It has been shown in various cancer studies that stanniocalcin-1 (STC1) is secreted by CAFs, however, its function in HCC is still not clear. Methods The serum concentration and intracellular expression level of STC1 were quantified by ELISA and western blotting, respectively. The role of CAF-derived STC1 in HCC stemness was investigated by sphere formation, sorafenib resistance, colony formation, and transwell migration and invasion assays in vitro and in an orthotopic liver xenograft model in vivo. An HCC tissue microarray containing 72 samples was used to evaluate the expression of STC1 and Notch1 in HCC tissues. Coimmunoprecipitation (CoIP) and dual-luciferase reporter assays were performed to further explore the underlying mechanisms. ELISAs were used to measure the serum concentration of STC1 in HCC patients. Results We demonstrated that CAFs were the main source of STC1 in HCC and that CAF-derived STC1 promoted HCC stemness through activation of the Notch signaling pathway. In HCC patients, the expression of STC1 was positively correlated with Notch1 expression and poor prognosis. The co-IP assay showed that STC1 directly bound to Notch1 receptors to activate the Notch signaling pathway, thereby promoting the stemness of HCC cells. Our data further demonstrated that STC1 was a direct transcriptional target of CSL in HCC cells. Furthermore, ELISA revealed that the serum STC1 concentration was higher in patients with advanced liver cancer than in patients with early liver cancer. Conclusions CAF-derived STC1 promoted HCC stemness via the Notch1 signaling pathway. STC1 might serve as a potential biomarker for the prognostic assessment of HCC, and the stromal-tumor amplifying STC1-Notch1 feedforward signal could constitute an effective therapeutic target for HCC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma

et al. 2023

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“…While past research has mainly highlighted the effects of DTX and CPT on tumor cells [ 40 , 71 ], the effects that such treatments may have on the stromal compartment still remain to be clarified. Among the numerous cellular components of the TME, CAFs are crucial actors during all the steps of tumorigenesis, thanks to the secretion of bioactive molecules which regulate tumor occurrence, development, metastasis, and therapeutic resistance [ 72 ]. Interestingly, senescent fibroblasts share many similarities with CAFs, and both strongly support the development of a pro-tumorigenic environment [ 22 , 73 , 74 , 75 , 76 , 77 ].…”

Section: Discussionmentioning

confidence: 99%

Therapy-Induced Stromal Senescence Promoting Aggressiveness of Prostate and Ovarian Cancer

Pardella¹,

Pranzini²,

Nesi³

et al. 2022

Cells

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Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy.

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“…[3] The compactness of the matrix is exacerbated in fibrotic tumors and results from excessive deposition of collagen fibers, produced by hyper-activated cancer-associated fibroblasts (CAFs). [4,5] This dense ECM limits the penetration of drugs and drug delivery systems out of the blood vessels into the tumor interstitium. [6,7] Increased ECM deposition can furthermore result in compression of tumor blood vessels, [8] thereby reducing tumor perfusion and hindering efficient drug access to and distribution in tumors, particularly in desmoplastic tumors such as in pancreatic cancer and certain types of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Repurposing Tamoxifen for Tumor Microenvironment Priming and Enhanced Tumor‐Targeted Drug Delivery

Biancacci,

De Santis,

Rama

et al. 2023

Advanced Therapeutics

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The dense stromal matrix in fibrotic tumors hinders tumor‐targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, is shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. It is investigated if TMX, administered in free and nano‐formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano‐formulations in pancreatic ductal adenocarcinoma and triple‐negative breast cancer mouse models, evaluated using clinical‐stage Cy7‐labeled core‐crosslinked polymeric micelles (CCPM). Under control conditions, higher levels of Cy7‐CCPM are found in PANC‐1 tumors (16.7% ID g−1 at 48 h post i.v. injection) than in 4T1 tumors (11.0% ID g−1). In both models, free and nano‐formulated TMX failed to improve CCPM delivery. These findings are congruent with the results from histopathological immunofluorescence analysis of tumor tissue, which indicate that TMX treatment does not significantly change vascularization, perfusion, macrophage infiltration, collagen density, and collagen fiber thickness. Altogether, these results demonstrate that in PANC‐1 and 4T1 mouse models, TMX treatment does not contribute to beneficial TME priming and enhanced tumor‐targeted drug delivery.

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Cancer-associated fibroblasts: Origin, function, imaging, and therapeutic targeting

Cited by 56 publications

References 379 publications

The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma

The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma

Therapy-Induced Stromal Senescence Promoting Aggressiveness of Prostate and Ovarian Cancer

Repurposing Tamoxifen for Tumor Microenvironment Priming and Enhanced Tumor‐Targeted Drug Delivery

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