Fibroblasts Promote Proliferation and Matrix Invasion of Breast Cancer Cells in Co‐Culture Models

Plaster, Madison; Singh, Sunil; Tavana, Hossein

doi:10.1002/adtp.201900121

Cited by 15 publications

(18 citation statements)

References 44 publications

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“…This characterization revealed that cancer cells crosstalk with HMFs resulted in an increase in MDA-MB-231s growth rate. Interestingly, these results are in agreement with recent literature demonstrating that normal breast fibroblasts that secrete high amounts of CXCL12, which is characteristic of our HMFs, induce MDA-MB-231 proliferation via the CXCR4 receptor [56]. On the other hand, we found an increase in nuclei counts in the HMFs co-cultured with the MDA-MB-231s.…”

Section: Discussionsupporting

confidence: 93%

Breast Fibroblasts and ECM Components Modulate Breast Cancer Cell Migration through the Secretion of MMPs in a 3D Microfluidic Co-Culture Model

Lugo-Cintrón

Gong

Ayuso

et al. 2020

Cancers

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The extracellular matrix (ECM) composition greatly influences cancer progression, leading to differential invasion, migration, and metastatic potential. In breast cancer, ECM components, such as fibroblasts and ECM proteins, have the potential to alter cancer cell migration. However, the lack of in vitro migration models that can vary ECM composition limits our knowledge of how specific ECM components contribute to cancer progression. Here, a microfluidic model was used to study the effect of 3D heterogeneous ECMs (i.e., fibroblasts and different ECM protein compositions) on the migration distance of a highly invasive human breast cancer cell line, MDA-MB-231. Specifically, we show that in the presence of normal breast fibroblasts, a fibronectin-rich matrix induces more cancer cell migration. Analysis of the ECM revealed the presence of ECM tunnels. Likewise, cancer-stromal crosstalk induced an increase in the secretion of metalloproteinases (MMPs) in co-cultures. When MMPs were inhibited, migration distance decreased in all conditions except for the fibronectin-rich matrix in the co-culture with human mammary fibroblasts (HMFs). This model mimics the in vivo invasion microenvironment, allowing the examination of cancer cell migration in a relevant context. In general, this data demonstrates the capability of the model to pinpoint the contribution of different components of the tumor microenvironment (TME).

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Section: Discussionsupporting

confidence: 93%

Breast Fibroblasts and ECM Components Modulate Breast Cancer Cell Migration through the Secretion of MMPs in a 3D Microfluidic Co-Culture Model

Lugo-Cintrón

Gong

Ayuso

et al. 2020

Cancers

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“…76 In a recent study, Plaster et al. 77 further developed this model by embedding the intermixed co-culture spheroids in a type I collagen matrix to study the interactions between TNBC cells and fibroblasts in presence of the ECM. This study also used CXCL12-CXCR4 signaling to model tumor–stromal interactions and showed that it significantly enhances proliferation of cancer cells while blocking it normalizes the effect.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional models of breast cancer–fibroblasts interactions

Singh

Tran

Putman

et al. 2020

Exp Biol Med (Maywood)

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Tumor microenvironment is a complex niche consisting of cancer cells and stromal cells in a network of extracellular matrix proteins and various soluble factors. Dynamic interactions among cellular and non-cellular components of the tumor microenvironment regulate tumor initiation and progression. Fibroblasts are the most abundant stromal cell type and dynamically interact with cancer cells both in primary tumors and in metastases. Cancer cells activate resident fibroblasts to produce and secrete soluble signaling molecules that support proliferation, migration, matrix invasion, and drug resistance of cancer cell and tumor angiogenesis. In recent years, various forms of three-dimensional tumor models have been developed to study tumor–stromal interactions and to identify anti-cancer drugs that block these interactions. There is currently a technological gap in development of tumor models that are physiologically relevant, scalable, and allow convenient, on-demand addition of desired components of the tumor microenvironment. In this review, we discuss three studies from our group that focus on developing bioengineered models to study tumor-stromal signaling. We will present these studies chronologically and based on their increasing complexity. We will discuss the validation of the models using a CXCL12-CXCR4 chemokine-receptor signaling present among activated fibroblasts and breast cancer cells in solid tumors, highlight the advantages and shortcomings of the models, and conclude with our perspectives on their applications. Impact statement Tumor stroma plays an important role in progression of cancers to a fatal metastatic disease. Modern treatment strategies are considering targeting tumor stroma to improve outcomes for cancer patients. A current challenge to develop stroma-targeting therapeutics is the lack of preclinical physiologic tumor models. Animal models widely used in cancer research lack human stroma and are not amenable to screening of chemical compounds for cancer drug discovery. In this review, we outline in vitro three-dimensional tumor models that we have developed to study the interactions among cancer cells and stromal cells. We describe development of the tumor models in a modular fashion, from a spheroid model to a sophisticated organotypic model, and discuss the importance of using correct physiologic models to recapitulate tumor-stromal signaling. These biomimetic tumor models will facilitate understanding of tumor-stromal signaling biology and provide a scalable approach for testing and discovery of cancer drugs.

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“…It enables stem cell transplantation and is used for hematologic malignancy and other diseases, such as bone marrow failure and sickle cell disease [ 95 ]. In cocultures of TNBC cells and BCAFs (both 2D and 3D), AMD3100 normalized cancer cell growth to the level observed in cells without any CXCL12 signaling [ 53 ]. Furthermore, CXCL12 and CXCR4 signaling stimulated cell growth and invasion, which was prevented by AMD3100 [ 53 ].…”

Section: Therapeutic Strategies Targeting Bcafsmentioning

confidence: 99%

“…BCAFs are involved in the progression, invasion, and metastasis of breast cancer, as well as chemotherapeutic resistance ( Figure 1 ) [ 28 , 51 ]. BCAF secretes a variety of growth factors and cytokines, such as the transforming growth factor β (TGF-β), VEGF, and the C-X-C motif chemokine ligand 12 (CXCL12) that promotes tumor growth, metastasis, and invasion [ 52 , 53 , 54 ]. BCAF secretes CXC-chemokine ligands 14 and 16 (CXCL14 and CXCL16).…”

Section: Introductionmentioning

confidence: 99%

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

Mollah

Varamini

2021

Biomedicines

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Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.

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Fibroblasts Promote Proliferation and Matrix Invasion of Breast Cancer Cells in Co‐Culture Models

Cited by 15 publications

References 44 publications

Breast Fibroblasts and ECM Components Modulate Breast Cancer Cell Migration through the Secretion of MMPs in a 3D Microfluidic Co-Culture Model

Breast Fibroblasts and ECM Components Modulate Breast Cancer Cell Migration through the Secretion of MMPs in a 3D Microfluidic Co-Culture Model

Three-dimensional models of breast cancer–fibroblasts interactions

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

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