Three-Dimensional Scaffolds to Evaluate Tumor Associated Fibroblast-Mediated Suppression of Breast Tumor Specific T Cells

Phan-Lai, Vy; Florczyk, Stephen J.; Kievit, Forrest M.; Wang, Kui; Gad, Ekram; Disis, Mary L.; Zhang, Miqin

doi:10.1021/bm301928u

Cited by 54 publications

(43 citation statements)

References 26 publications

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“…These CA scaffolds can provide the medium for these studies. Additionally, these CA scaffolds can be used to probe the specific microenvironmental cues (cellular and non-cellular [10, 11, 31–33]) that promote the conversion of non-CSCs into CSCs to generate effective microenvironmental therapies.…”

Section: Discussionmentioning

confidence: 99%

Proliferation and enrichment of CD133+ glioblastoma cancer stem cells on 3D chitosan-alginate scaffolds

et al. 2014

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Emerging evidence implicates cancer stem cells (CSCs) as primary determinants of the clinical behavior of human cancers, representing an ideal target for next-generation anticancer therapies. However CSCs are difficult to propagate in vitro, severely limiting the study of CSC biology and drug development. Here we report that growing cells from glioblastoma (GBM) cell lines on three dimensional (3D) porous chitosan-alginate (CA) scaffolds dramatically promotes the proliferation and enrichment of cells possessing the hallmarks of CSCs. CA scaffold-grown cells were found more tumorigenic in nude mouse xenografts than cells grown from monolayers. Growing in CA scaffolds rapidly promoted expression of genes involved in the epithelial-to-mesenchymal transition that has been implicated in the genesis of CSCs. Our results indicate that CA scaffolds have utility as a simple and inexpensive means to cultivate CSCs in vitro in support of studies to understand CSC biology and develop more effective anti-cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Proliferation and enrichment of CD133+ glioblastoma cancer stem cells on 3D chitosan-alginate scaffolds

et al. 2014

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“…For example, a 3D model of mouse mammary carcinoma cells cultured in porous chitosan-alginate scaffolds was used to evaluate CTL function in the presence or absence of tumor-associated fibroblasts. It was found fibroblasts decreased tumor necrosis factor α (TNFα) secretion by CTLs, likely due to elevated production of IL-10 and transforming growth factor beta (TGF-β) in the co-cluture 75 . In another study, drug inhibition of tumor cell-macrophage paracrine interactions was analyzed using co-culture of breast adenocarcinoma cells and macrophages in alginate hydrogel fibers.…”

Section: Biomaterials To Create 3d Tumor Modelsmentioning

confidence: 99%

Biomaterials and emerging anticancer therapeutics: engineering the microenvironment

2015

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The microenvironment is increasingly recognized to play key roles in cancer, and biomaterials provide a means to engineer microenvironments both in vitro and in vivo to study and manipulate cancer. In vitro cancer models using 3D matrices recapitulate key elements of the tumor microenvironment and have revealed new aspects of cancer biology. Cancer vaccines based on some of the same biomaterials have, in parallel, allowed for the engineering of durable prophylactic and therapeutic anticancer activity in preclinical studies, and some of these vaccines have moved to clinical trials. The impact of biomaterials engineering on cancer treatment is expected to further increase in importance in the years to come.

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“…As an example, CAF recruitment and the initiation of fibrosis typically are events associated with the inflammatory response [139]. Being a major component of the tumor stroma, CAFs not only physically impede the penetration of antitumor T cell into the tumor but also modulates immune function via the secretion of numerous cytokines and chemokines [139, 141]. Taking one step further in complexity, Phan-Lai et al developed a tri-culture system to investigate the effect of CAFs on T lymphocyte function in the presence of breast cancer cells [141].…”

Section: Modeling the Complex Tumor Microenvironment In 3dmentioning

confidence: 99%

“…Being a major component of the tumor stroma, CAFs not only physically impede the penetration of antitumor T cell into the tumor but also modulates immune function via the secretion of numerous cytokines and chemokines [139, 141]. Taking one step further in complexity, Phan-Lai et al developed a tri-culture system to investigate the effect of CAFs on T lymphocyte function in the presence of breast cancer cells [141]. Using 3D chitosan-alginate scaffolds for the tri-culture and using TNF-α as a measure of helper T cell activation, it was found that the presence of CAFs impaired the ability of the T cells to secrete TNF-α, highlighting the immunosuppressive role of CAFs in this system.…”

Section: Modeling the Complex Tumor Microenvironment In 3dmentioning

confidence: 99%

Heralding a new paradigm in 3D tumor modeling

et al. 2016

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Numerous studies to date have contributed to a paradigm shift in modeling cancer, moving from the traditional two-dimensional culture system to three-dimensional (3D) culture systems for cancer cell culture. This led to the inception of tumor engineering, which has undergone rapid advances over the years. In line with the recognition that tumors are not merely masses of proliferating cancer cells but rather, highly complex tissues consisting of a dynamic extracellular matrix together with stromal, immune and endothelial cells, significant efforts have been made to better recapitulate the tumor microenvironment in 3D. These approaches include the development of engineered matrices and co-cultures to replicate the complexity of tumor-stroma interactions in vitro. However, the tumor engineering and cancer biology fields have traditionally relied heavily on the use of cancer cell lines as a cell source in tumor modeling. While cancer cell lines have contributed to a wealth of knowledge in cancer biology, the use of this cell source is increasingly perceived as a major contributing factor to the dismal failure rate of oncology drugs in drug development. Backing this notion is the increasing evidence that tumors possess intrinsic heterogeneity, which predominantly homogeneous cancer cell lines poorly reflect. Tumor heterogeneity contributes to therapeutic resistance in patients. To overcome this limitation, cancer cell lines are beginning to be replaced by primary tumor cell sources, in the form of patient-derived xenografts and organoids cultures. Moving forward, we propose that further advances in tumor engineering would require that tumor heterogeneity (tumor variants) be taken into consideration together with tumor complexity (tumor-stroma interactions). In this review, we provide a comprehensive overview of what has been achieved in recapitulating tumor complexity, and discuss the importance of incorporating tumor heterogeneity into 3D in vitro tumor models. This work carves out the roadmap for 3D tumor engineering and highlights some of the challenges that need to be addressed as we move forward into the next chapter.

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Three-Dimensional Scaffolds to Evaluate Tumor Associated Fibroblast-Mediated Suppression of Breast Tumor Specific T Cells

Cited by 54 publications

References 26 publications

Proliferation and enrichment of CD133+ glioblastoma cancer stem cells on 3D chitosan-alginate scaffolds

Proliferation and enrichment of CD133+ glioblastoma cancer stem cells on 3D chitosan-alginate scaffolds

Biomaterials and emerging anticancer therapeutics: engineering the microenvironment

Heralding a new paradigm in 3D tumor modeling

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