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Three-dimensional tumor model mimics stromal - breast cancer cells signaling.

ABSTRACT: Tumor stroma is a major contributor to the biological aggressiveness of cancer cells. Cancer cells induce activation of normal fibroblasts to carcinoma-associated fibroblasts (CAFs), which promote survival, proliferation, metastasis, and drug resistance of cancer cells. A better understanding of these interactions could lead to new, targeted therapies for cancers with limited treatment options, such as triple negative breast cancer (TNBC). To overcome limitations of standard monolayer cell cultures and xenograft models that lack tumor complexity and/or human stroma, we have developed a high throughput tumor spheroid technology utilizing a polymeric aqueous two-phase system to conveniently model interactions of CAFs and TNBC cells and quantify effects on signaling and drug resistance of cancer cells. We focused on signaling by chemokine CXCL12, a hallmark molecule secreted by CAFs, and receptor CXCR4, a driver of tumor progression and metastasis in TNBC. Using three-dimensional stromal-TNBC cells cultures, we demonstrate that CXCL12 - CXCR4 signaling significantly increases growth of TNBC cells and drug resistance through activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Despite resistance to standard chemotherapy, upregulation of MAPK and PI3K signaling sensitizes TNBC cells in co-culture spheroids to specific inhibitors of these kinase pathways. Furthermore, disrupting CXCL12 - CXCR4 signaling diminishes drug resistance of TNBC cells in co-culture spheroid models. This work illustrates the capability to identify mechanisms of drug resistance and overcome them using our engineered model of tumor-stromal interactions.

SUBMITTER: Ham SL

PROVIDER: S-EPMC5787462 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Three-dimensional tumor model mimics stromal - breast cancer cells signaling.

Ham Stephanie Lemmo SL Thakuri Pradip Shahi PS Plaster Madison M Li Jun J Luker Kathryn E KE Luker Gary D GD Tavana Hossein H

Oncotarget 20171205 1

Tumor stroma is a major contributor to the biological aggressiveness of cancer cells. Cancer cells induce activation of normal fibroblasts to carcinoma-associated fibroblasts (CAFs), which promote survival, proliferation, metastasis, and drug resistance of cancer cells. A better understanding of these interactions could lead to new, targeted therapies for cancers with limited treatment options, such as triple negative breast cancer (TNBC). To overcome limitations of standard monolayer cell cultu ...[more]

PMID: 29416611

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Project description:BACKGROUND: Transforming growth factor (TGF)-? plays a pivotal role in cancer progression through regulating cancer cell proliferation, invasion, and remodeling of the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are the predominant type of stromal cell, in which TGF-? signaling is activated. Among the strategies for TGF-? signaling inhibition, RNA interference (RNAi) targeting of TGF-? ligands is emerging as a promising tool. Although preclinical studies support the efficacy of this therapeutic strategy, its effect on the tumor microenvironment in vivo remains unknown. In addition, differential effects due to knockdown of various TGF-? ligand isoforms have not been examined. Therefore, an experimental model that recapitulates tumor-stromal interaction is required for validation of therapeutic agents. METHODS: We have previously established a three-dimensional co-culture model of lung cancer, and demonstrated the functional role of co-cultured fibroblasts in enhancing cancer cell invasion and differentiation. Here, we employed this model to examine how knockdown of TGF-? ligands affects the behavior of different cell types. We developed lentivirus vectors carrying artificial microRNAs against human TGF-?1 and TGF-?2, and tested their effects in lung cancer cells and fibroblasts. RESULTS: Lentiviral vectors potently and selectively suppressed the expression of TGF-? ligands, and showed anti-proliferative effects on these cells. Furthermore, knockdown of TGF-? ligands attenuated fibroblast-mediated collagen gel contraction, and diminished lung cancer cell invasion in three-dimensional co-culture. We also observed differential effects by targeting different TGF-? isoforms in lung cancer cells and fibroblasts. CONCLUSIONS: Our findings support the notion that RNAi-mediated targeting of TGF-? ligands may be beneficial for lung cancer treatment via its action on both cancer and stromal cells. This study further demonstrates the usefulness of this three-dimensional co-culture model to examine the effect of therapeutic agents on tumor-stromal interaction.

Dataset Information

Three-dimensional tumor model mimics stromal - breast cancer cells signaling.

Publications

Three-dimensional tumor model mimics stromal - breast cancer cells signaling.

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