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Tumor-stroma interactions differentially alter drug sensitivity based on the origin of stromal cells.

ABSTRACT: Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large-scale coculture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor-stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.

SUBMITTER: Landry BD

PROVIDER: S-EPMC6078165 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Tumor-stroma interactions differentially alter drug sensitivity based on the origin of stromal cells.

Landry Benjamin D BD Leete Thomas T Richards Ryan R Cruz-Gordillo Peter P Schwartz Hannah R HR Honeywell Megan E ME Ren Gary G Schwartz Alyssa D AD Peyton Shelly R SR Lee Michael J MJ

Molecular systems biology 20180806 8

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large-scale coculture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our dat ...[more]

PMID: 30082272

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Project description:BackgroundExisting high-risk factors are insufficient to accurately predict the postoperative recurrence risk of stage II colorectal cancer (CRC). The discovery of additional prognostic markers may be the key to improving the current status of stage II CRC treatment. The present study aimed to evaluate the relationship among desmoplastic reaction (DR), tumor budding (TBd), the tumor-stroma ratio (TSR) and their prognostic value for relapse-free survival (RFS).MethodsIn this study, 207 patients with histologically confirmed stage II CRC from January 2012 to August 2018 were retrospectively reviewed from a single center; the cohort was divided into subgroups based on low or high TSR, and low, intermediate or high DR and TBd. Kaplan-Meier curve analysis and log-rank test were applied to examine RFS among subgroups. Univariate and multivariate Cox proportional hazards analyses were used to identify independent factors associated with RFS, and a nomogram was subsequently developed.ResultsAbnormal CA242, CEA, T4 stage, presence of hypertension, internal obstruction or perforation (IOP), lymphovascular or/and perineural invasion (PNI), number of nodes examined less than 12, low-frequency microsatellite instability (MSI-L), higher Ki-67 and immature DR were associated with a lower RFS. In multivariable analysis, DR (HR =2.111; 95% CI: 1.184-3.766; P=0.011), LVI (HR =1.919; 95% CI: 1.004-3.669; P=0.049) and PNI (HR =2.724; 95% CI: 1.362-5.448; P=0.005) were prognostic factors for RFS. On this basis, a nomogram that integrated DR and clinicopathologic predictors for predicting RFS passed the calibration and had an area under the curve of 0.826.ConclusionsThe prognostic significance of DR outperformed TBd and TSR, therefore, we recommend adding DR as a biomarker in routine pathological reports. The novel nomogram combining these factors may be used as a reliable and effective tool for the prediction of RFS in stage II CRC, thus helping optimize therapeutic regimens under cooperation of oncologists and surgeons. Further multicentric studies are required for validation of this novel, simple and cost-effective prognostic model.

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Tumor-stroma interactions differentially alter drug sensitivity based on the origin of stromal cells.

Publications

Tumor-stroma interactions differentially alter drug sensitivity based on the origin of stromal cells.

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