Paracrine Crosstalk between Fibroblasts and ER+ Breast Cancer Cells Creates an IL1β-Enriched Niche that Promotes Tumor Growth

Chatterjee, Sumanta; Bhat, Vasudeva; Бердников, А. В.; Liu, Jiahui; Buchel, Edward W.; Safneck, Janice R.; Marshall, Aaron J.; Murphy, Leigh C.; Postovit, Lynne-Marie; Raouf, Afshin

doi:10.1016/j.isci.2019.07.034

Cited by 32 publications

(22 citation statements)

References 45 publications

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“…Based on preliminary titration studies performed in our lab and on other in vitro reports using TNFα [ 97 , 98 , 99 ] and IL-1β [ 100 , 101 ], MSCs were stimulated by recombinant human (rh) TNFα (50 ng/mL; #300-01A, PeproTech, NJ, USA) and/or rhIL-1β (0.5 ng/mL; #200-01B, PeproTech). Control cells were treated by the vehicles of the cytokines.…”

Section: Methodsmentioning

confidence: 99%

Persistent Inflammatory Stimulation Drives the Conversion of MSCs to Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast Cancer Cells

Rubinstein-Achiasaf

Morein

Ben-Yaakov

et al. 2021

Cancers

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The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo conversion at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNFα + IL-1β (generally 14–18 days) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased abilities to contract collagen gels. Moreover, they gained the phenotype of inflammatory CAFs, as indicated by the reduced expression of α smooth muscle actin (αSMA), increased proliferation, and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell dispersion, scattering, and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5, and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation can induce MSC-to-CAF conversion, leading to the generation of tumor-promoting inflammatory CAFs.

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Section: Methodsmentioning

confidence: 99%

Persistent Inflammatory Stimulation Drives the Conversion of MSCs to Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast Cancer Cells

Rubinstein-Achiasaf

Morein

Ben-Yaakov

et al. 2021

Cancers

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“…Among TME cell types, CAFs constitute the major stromal component of many breast cancers and have recently emerged as potential therapeutic targets 6 , 7 , 8 . Fibroblasts are the main producers of ECM and play fundamental roles in tissue repair, during which they acquire an activated myofibroblast phenotype characterized by α-smooth muscle actin (α-SMA) expression [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Embryonic protein NODAL regulates the breast tumor microenvironment by reprogramming cancer-derived secretomes

et al. 2021

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The tumor microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumorigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumor growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple-negative breast cancers and that it directly induces Cancer-associated fibroblasts phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g., CXCL1), cytokines (e.g., IL-6) and growth factors (e.g., PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.

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“…Currently available models of the breast cancer microenvironment often incorporate particular immune subpopulations, such as monocytes [ 175 , 176 , 177 , 178 ], T cells [ 179 , 180 ], or NK cells [ 180 , 181 ], to capture the reciprocal influence of immune and tumor cells in the suppressive environment [ 175 , 176 , 177 , 178 , 181 ] but also to assess the anti-tumor capacity of killer cells [ 179 , 180 ]. In another approach, several groups have developed models containing distinct immune cell types for drug testing in the TME of different breast cancer subtypes [ 182 , 183 ]. These studies heighten the promise of advanced heterotypic cell models for predictive pre-clinical and co-clinical studies.…”

Section: Experimental Models To Interrogate Tumor–immune Interactimentioning

confidence: 99%

The Peripheral Immune Landscape of Breast Cancer: Clinical Findings and In Vitro Models for Biomarker Discovery

Batalha

Cristóvão-Ferreira²,

Brito

2021

Cancers

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Breast cancer is the deadliest female malignancy worldwide and, while much is known about phenotype and function of infiltrating immune cells, the same attention has not been paid to the peripheral immune compartment of breast cancer patients. To obtain faster, cheaper, and more precise monitoring of patients’ status, it is crucial to define and analyze circulating immune profiles. This review compiles and summarizes the disperse knowledge on the peripheral immune profile of breast cancer patients, how it departs from healthy individuals and how it changes with disease progression. We propose this data to be used as a starting point for validation of clinically relevant biomarkers of disease progression and therapy response, which warrants more thorough investigation in patient cohorts of specific breast cancer subtypes. Relevant clinical findings may also be explored experimentally using advanced 3D cellular models of human cancer–immune system interactions, which are under intensive development. We review the latest findings and discuss the strengths and limitations of such models, as well as the future perspectives. Together, the scientific advancement of peripheral biomarker discovery and cancer–immune crosstalk in breast cancer will be instrumental to uncover molecular mechanisms and putative biomarkers and drug targets in an all-human setting.

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Paracrine Crosstalk between Fibroblasts and ER+ Breast Cancer Cells Creates an IL1β-Enriched Niche that Promotes Tumor Growth

Cited by 32 publications

References 45 publications

Persistent Inflammatory Stimulation Drives the Conversion of MSCs to Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast Cancer Cells

Persistent Inflammatory Stimulation Drives the Conversion of MSCs to Inflammatory CAFs That Promote Pro-Metastatic Characteristics in Breast Cancer Cells

Embryonic protein NODAL regulates the breast tumor microenvironment by reprogramming cancer-derived secretomes

The Peripheral Immune Landscape of Breast Cancer: Clinical Findings and In Vitro Models for Biomarker Discovery

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