Cancer-associated fibroblasts as target and tool in cancer therapeutics and diagnostics

Vlieghere, Elly De; Verset, Laurine; Demetter, Pieter; Bracke, Marc; Wever, Olivier De

doi:10.1007/s00428-015-1818-4

Cited by 39 publications

(77 citation statements)

References 115 publications

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“…Accumulating evidences demonstrate that CAFs play a prominent role in tumor growth and progression, and could be a promising tool to cancer therapeutics [26]. Therefore, a better understanding of the molecular mechanism for the tumor-promoting prosperities of CAFs is of obvious importance for understanding in gastric cancer progression and finding novel strategies to it.…”

Section: Discussionmentioning

confidence: 99%

IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway

et al. 2017

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Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Here, we show that CAFs isolated from gastric cancer produce significant amounts of interleukin-6 (IL-6). CAFs enhances the migration and EMT of gastric cancer cells through the secretion of IL-6 that activates Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in gastric cancer cells, while deprivation of IL-6 using a neutralizing antibody or inhibition of JAK/STAT3 pathway with specific inhibitor AG490 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs. Moreover, silencing IL-6 expression in CAFs or inhibiting JAK2/STAT3 pathway in gastric cancer cells impairs tumor peritoneal metastasis induced by CAFs in vivo. Taken together, these results suggest that CAFs in the tumor microenvironment promote the progression of gastric cancer through IL-6/JAK2/STAT3 signaling, and IL-6 targeted therapy could be a complementary approach against gastric cancer by exerting their action on stromal fibroblasts.

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Section: Discussionmentioning

confidence: 99%

IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway

et al. 2017

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“…Given the large amount of NPs delivered to fibroblasts, we hypothesized that we could take advantage of this natural property of bladder and pancreatic cancers and target cancer treatment through fibroblasts. Inspired by fibroblast’s ability to secrete tumor supportive cytokines to neighboring tumor cells (46,47), modification of fibroblasts to secrete tumor suppressive cytokines through gene delivery with NPs was proposed in the current manuscript. The in situ engineering of fibroblasts harnesses the location of fibroblasts between blood vessels and tumor cells, bypassing major cellular barriers for NP delivery; subsequently converting fibroblasts from a tumor supporting role to a tumor depletion center.…”

Section: Discussionmentioning

confidence: 99%

Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors

et al. 2017

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The off-target distribution of anticancer nanoparticles (NP) to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this NP detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes (LPD) and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate ~70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Further, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well-known to be a major barrier to the delivery of therapeutic NP. Collectively, our results offer a proof of concept for the use of NP to modify TAFs as an effective strategy to treat desmoplastic cancers.

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“…In contrast to cancer cells, as the interaction between cancer cells and their environment is probably universal across different tumor types, therapies targeting tumor-microenviroment interactions should be applicable to a large group of patients and they should be less likely to acquire drug resistance because the cancer stroma shows less phenotypic drifts [32]. Currently, TGF-b signaling is considered a key regulator in CAF activation or stromal gene expression [28,29,33]; therefore, many investigators have tried to inhibit the influence of the cancer stroma using anti-TGF-b therapies.…”

Section: Discussionmentioning

confidence: 99%

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

et al. 2016

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Objective The aim of this study was to evaluate the prognostic significance of the intratumor stromal proportion in gastric signet ring cell (SRC) carcinomas. Background Cancer stroma, as exemplified by cancer-associated fibroblasts (CAFs), plays critical roles in cancer proliferation, invasion, and metastasis. Methods One hundred seventy-five SRC carcinoma cases were classified according to the intratumor desmoplastic stromal proportion to then analyze the clinicopathologic characteristics of stroma-rich cases. We also investigated the impact of CAFs on the migration as well as on the phenotypic changes of gastric SRC carcinomas in vitro.Furthermore, we performed RNA sequencing of a pair of CAFs and normal-tissue-associated fibroblasts. Results Stroma-rich SRC carcinomas (64 of 175 cases, 36.5%) were associated with female patients (P = 0.045), large tumor size (P = 0.007), higher T category (P \ 0.001), and the presence of perineural invasion (P = 0.018). Patients with stroma-rich SRC carcinomas had a significantly shorter disease-free survival (P \ 0.001) and overall survival (P \ 0.001). However, in a subgroup analysis, the prognostic significance of the stromal proportion correlated only with patients with T3/4 disease. From multivariate analysis, the high stromal proportion is an independent prognostic factor to predict worse disease-free survival (hazard ratio 2.288; P = 0.001) and overall survival (hazard ratio 2.503; P = 0.001). We found that CAFs enhanced the migratory abilities of cancer cells through the epithelial-mesenchymal transition, and RNA sequencing results confirmed these findings. Conclusions The intratumor stromal proportion could be a useful prognostic biomarker and a potential therapeutic target in gastric SRC carcinomas.

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Cancer-associated fibroblasts as target and tool in cancer therapeutics and diagnostics

Cited by 39 publications

References 115 publications

IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway

IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway

Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

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