Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

Louault, Kévin; Li, Rongrong; DeClerck, Yves A.

doi:10.3390/cancers12113108

Cited by 99 publications

(103 citation statements)

References 208 publications

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“…To follow up on our above findings demonstrating that the continuous TNFα + IL-1β stimulation leads to the generation of CAFs and in view of recent studies on CAF plasticity [ 36 , 37 , 38 , 39 ], we then asked what is the phenotype of the inflammation-driven CAFs. In line with the characteristics of inflammatory CAFs identified in pancreatic ductal adenocarcinoma (PDAC) and the major roles of IL-1 in their generation [ 50 , 51 ], we found out that the inflammation-driven CAFs expressed typical phenotypic characteristics of inflammatory CAFs.…”

Section: Resultsmentioning

confidence: 99%

“…The identity of the cells as inflammatory CAFs was based on a gradual analysis that we performed, demonstrating that, following continuous stimulation of MSCs by TNFα + IL-1β, the resulting cells expressed a CAF-like morphology, thus showing that they expressed typical CAF markers and functions, and ultimately that the resulting CAFs expressed the phenotype of inflammatory CAFs. The identification of the cells as inflammatory CAFs is of interest in view of recent reports that have provided evidence of the immense plasticity of CAFs [ 36 , 37 , 38 , 39 ]. For example, inflammatory CAFs have been identified in PDAC by the Tuveson group, demonstrating that these cells are located in desmoplastic areas of the tumors, are enriched with the expression of pro-inflammatory mediators such as IL-6 and LIF and are generated by IL-1 signaling [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…Among others, bone marrow (BM)-derived MSCs are known to be recruited to the tumor area, where they exert many tumor-promoting activities and undergo conversion to cancer-associated fibroblasts (CAFs) [ 12 , 14 , 29 , 30 , 31 , 32 , 33 ]; in general, these activated fibroblasts were reported as being heavily engaged in pro-metastatic tasks [ 11 , 33 , 34 , 35 ]. Recent studies provided evidence of the existence of heterogeneous CAF populations that can reside side by side in tumors, expressing different markers and functions [ 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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“…Normalized lipid count values for biological replicates were integrated using ComBat [57] to correct batch effects. Batch corrected counts per each lipid were then scaled by their average.…”

Section: Competing Interestsmentioning

confidence: 99%

Sphingolipid Control of Fibroblast Heterogeneity Revealed by Single-Cell Lipidomics

Capolupo

Khven

Mazzeo

et al. 2021

Preprint

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Human cells produce thousands of lipids that impact a wide range of biological processes in ways we are only starting to characterize. The cellular composition in lipids changes during differentiation events and also varies across individual cells of the same type. Yet, the precise differences in lipid composition that directly affect cell phenotypes remain unknown. Here we have measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging to single-cell transcriptomics. We found that the cell-to-cell variation of specific lipid metabolic pathways contributes to the establishment of cell states involved in wound repair and in skin cancer growth. Sphingolipid composition defined fibroblast subpopulations while sphingolipid metabolic rewiring drove cell state transitions. These data uncover a role for cell-to-cell lipid heterogeneity in the determination of cell states and reveal a new regulatory component to the homeostasis and self-organization of multicellular systems.

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“…Additionally, the flavonoid nobiletin and the triterpenoid cucurbitacin B exerted antiangiogenic effects in breast cancer cells and xenograft mouse models downregulating FAK-dependent signaling pathways and expression of neovasculature markers [ 172 , 173 ]. Several investigations have elucidated the involvement of FAK toward the protumorigenic functions mediated by CAFs in diverse tumors, including breast cancer [ 174 , 175 , 176 , 177 , 178 ]. Of note, the role of FAK in the bidirectional communication between CAFs and breast cancer cells has been recently investigated [ 175 ].…”

Section: Fak and The Breast Tmementioning

confidence: 99%

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

Rigiracciolo

Cirillo

Talia

et al. 2021

Cancers

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Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors.

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Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

Cited by 99 publications

References 208 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

Sphingolipid Control of Fibroblast Heterogeneity Revealed by Single-Cell Lipidomics

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

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