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Fibroblasts in the Tumor Microenvironment: Shield or Spear?

ABSTRACT: Tumorigenesis is a complex process involving dynamic interactions between malignant cells and their surrounding stroma, including both the cellular and acellular components. Within the stroma, fibroblasts represent not only a predominant cell type, but also a major source of the acellular tissue microenvironment comprising the extracellular matrix (ECM) and soluble factors. Normal fibroblasts can exert diverse suppressive functions against cancer initiating and metastatic cells via direct cell-cell contact, paracrine signaling by soluble factors, and ECM integrity. The loss of such suppressive functions is an inherent step in tumor progression. A tumor cell-induced switch of normal fibroblasts into cancer-associated fibroblasts (CAFs), in turn, triggers a range of pro-tumorigenic signals accompanied by distraction of the normal tissue architecture, thus creating an optimal niche for cancer cells to grow extensively. To further support tumor progression and metastasis, CAFs secrete factors such as ECM remodeling enzymes that further modify the tumor microenvironment in combination with the altered adhesive forces and cell-cell interactions. These paradoxical tumor suppressive and promoting actions of fibroblasts are the focus of this review, highlighting the heterogenic molecular properties of both normal and cancer-associated fibroblasts, as well as their main mechanisms of action, including the emerging impact on immunomodulation and different therapy responses.

SUBMITTER: Alkasalias T

PROVIDER: S-EPMC5983719 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Fibroblasts in the Tumor Microenvironment: Shield or Spear?

Alkasalias Twana T Moyano-Galceran Lidia L Arsenian-Henriksson Marie M Lehti Kaisa K

International journal of molecular sciences 20180521 5

Tumorigenesis is a complex process involving dynamic interactions between malignant cells and their surrounding stroma, including both the cellular and acellular components. Within the stroma, fibroblasts represent not only a predominant cell type, but also a major source of the acellular tissue microenvironment comprising the extracellular matrix (ECM) and soluble factors. Normal fibroblasts can exert diverse suppressive functions against cancer initiating and metastatic cells via direct cell-c ...[more]

PMID: 29883428

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Project description:Despite compelling evidence linking voluntary medical male circumcision (VMMC) with 60-70% HIV risk reduction in sub-Saharan Africa, Zambian men have been especially reluctant to undergo VMMC. The Government of Zambia set targets for VMMC uptake and promoted community-level interventions. Spear & Shield (S&S) is an innovative, evidence-based, service program promoting VMMC uptake while ensuring both VMMC supply and demand. This study assessed the large-scale provincial rollout of the program (S&S2) utilizing the RE-AIM model for translating interventions into the community. The S&S2 study was conducted between November 2015 and December 2020, and sequentially rolled out over four Zambian provinces in 96 clinics; 24 observation clinics received VMMC training only. Local clinic healthcare workers were trained to conduct the VMMC procedure and HIV counselors were trained to lead S&S group sessions. Using the RE-AIM model, primary outcomes were: Reach, the number, proportion, and representativeness of S&S attendees; Effectiveness, the impact of S&S2 on VMMC uptake; Adoption, the number, proportion, and representativeness of clinics implementing S&S2; Implementation, fidelity to the S&S intervention manual; and Maintenance, the extent to which S&S2 became an element of standard care within community clinics. Initially, n = 109 clinics were recruited; 96 were sustained and randomized for activation (Adoption). A total of 45,630 clinic patients (n = 23,236 men and n = 22,394 women) volunteered to attend the S&S sessions (Reach). The S&S2 program ran over 2,866 clinic-months (Implementation). Although the study did not target individual-level VMMCs, ~58,301 additional VMMCs were conducted at the clinic level (Effectiveness). Fidelity to the S&S intervention by group leaders ranged from 42%-95%. Sustainability of the program was operationalized as the number of CHCs initially activated that sustained the program. Intervention delivery ended, however, when study funding ceased (Maintenance). The S&S2 program successfully utilized the RE-AIM model to achieve study goals for implementation and dissemination in four Zambian provinces. Innovative VMMC programs such as S&S2 can improve the uptake of VMMC, one of the most effective strategies in the HIV prevention arsenal.

Project description:BackgroundVoluntary medical male circumcision (VMMC) is an important HIV prevention strategy, particularly in regions with high HIV incidence and low rates of male circumcision. However, 88% of the Zambian male population remain uncircumcised, and of these 80% of men surveyed expressed little interest in undergoing VMMC.MethodsThe Spear and Shield study (consisting of 4 weekly, 90-minute sexual risk reduction/VMMC promotion sessions) recruited and enrolled men (N = 800) who self-identified as at risk of HIV by seeking HIV testing and counseling at community health centers. Eligible men tested HIV-negative, were uncircumcised, and expressed no interest in VMMC. Participants were encouraged (but not required) to invite their female partners (N = 668) to participate in the program in a gender-concordant intervention matched to their partners'. Men completed assessments at baseline, post-intervention (about 2 months after baseline), and 6 and 12 months post-intervention; women completed assessments at baseline and post-intervention. For those men who underwent VMMC and for their partners, an additional assessment was conducted 3 months following the VMMC. The ancillary analysis in this article compared the pre- and post-VMMC responses of the 257 Zambian men who underwent circumcision during or following study participation, using growth curve analyses, as well as of the 159 female partners.ResultsMen were satisfied overall with the procedure (mean satisfaction score, 8.4 out of 10), and nearly all men (96%) and women (94%) stated they would recommend VMMC to others. Approximately half of the men reported an increase or no change in erections, orgasms, and time to achieve orgasms from pre-VMMC, while one-third indicated fewer erections and orgasms and decreased time to achieve orgasms post-VMMC. Nearly half (42%) of the men, and a greater proportion (63%) of the female partners, said their sexual pleasure increased while 22% of the men reported less sexual pleasure post-VMMC. Growth curve analysis of changes in sexual functioning and satisfaction over time revealed no changes in erectile functioning or intercourse satisfaction, but there were increases in orgasm functioning, overall sexual satisfaction, and sexual desire. The majority (61% to 70%) of men and women thought penile cleanliness and appearance had improved post-VMMC. Of the 69% of men who reported having sexual intercourse at least once between having the procedure and their 3-month post-VMMC assessment, the large majority (76%) waited at least 6 weeks before resuming sex. Sexual intercourse prior to the 6-week healing period was associated with adverse events and lower levels of post-VMMC sexual satisfaction.ConclusionBoth men and their partners can generally expect equal or improved sexual satisfaction and penile hygiene following VMMC. Future studies should consider innovative strategies to assist men in their efforts to abstain from sexual activities prior to complete healing.

Project description:The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6R?) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6R? antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6R? overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6R? and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.Significance: These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. Cancer Res; 78(17); 4957-70. ©2018 AACR.

Dataset Information

Fibroblasts in the Tumor Microenvironment: Shield or Spear?

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Fibroblasts in the Tumor Microenvironment: Shield or Spear?

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