Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4

Aronovich, Anna; Moyal, Lilach; Gorovitz, Batia; Amitay‐Laish, Iris; Naveh, Hadas Prag; Forer, Yaara; Maron, Lea; Knaneh, Jamal; Ad‐El, Dean; Yaacobi, Dafna Shilo; Barel, Eric; Erez, Neta; Hodak, Emmilia

doi:10.1016/j.jid.2020.06.034

Cited by 32 publications

(19 citation statements)

References 48 publications

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“…We also showed that fibroblasts in MF differ from normal fibroblasts in the expression of FAPα, a known CAF marker. We observe expression in MF fibroblasts that is consistent with the previous report of FAP-α in MF lesions [34]. Furthermore, the current study shows increasing expression of FAP-α in more advanced MF stages, and demonstrates for the first time that FAP-α expression can be correlated to stage (Fig.…”

Section: Discussionsupporting

confidence: 92%

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Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma

2021

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Background Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. The role of the skin microenvironment in MF development is unclear, but recent findings in a variety of cancers have highlighted the role of stromal fibroblasts in promoting or inhibiting tumorigenesis. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Here we describe studies into the interaction of TME-fibroblasts and malignant T cells to gain insight into their role in CTCL. Methods Skin from normal (n = 3) and MF patients (n = 3) were analyzed for FAPα by immunohistochemistry. MyLa is a CTCL cell line that retains expression of biomarkers TWIST1 and TOX that are frequently detected in CTCL patients. MyLa cells were cultured in the presence or absence of normal or MF skin derived fibroblasts for 5 days, trypsinized to detached MyL a cells, and gene expression analyzed by RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 markers (IFNG, TBX21), Th2 markers (GATA3, IL16), and proliferation marker (MKI67). Purified fibroblasts were assayed for VIM and ACTA2 gene expression. Cellular senescence assay was performed to assess senescence. Results MF skin fibroblast showed increased expression of FAP-α with increasing stage compared to normal. Normal fibroblasts co-cultured with MyLa cells suppressed expression of TWIST1 (p < 0.0006), and TOX (p < 0.03), GATA3 (p < 0.02) and IL16 (p < 0.03), and increased expression of IFNG (p < 0.03) and TBX21 (p < 0.03) in MyLa cells. In contrast, MyLa cells cultured with MF fibroblasts retained high expression of TWIST1, TOX and GATA3. MF fibroblasts co-culture with MyLa cells increased expression of IL16 (p < 0.01) and IL4 (p < 0.02), and suppressed IFNG and TBX21 in MyLa cells. Furthermore, expression of MKI67 in MyLa cells was suppressed by normal fibroblasts compared to MF fibroblasts. Conclusion Skin fibroblasts represent important components of the TME in MF. In co-culture model, normal and MF fibroblasts have differential influence on T-cell phenotype in modulating expression of Th1 cytokine and CTCL biomarker genes to reveal distinct roles with implications in MF progression.

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Section: Discussionsupporting

confidence: 92%

“…31], MMP21[32], TGFA[33], CXCL12[34], ITGA3[35], FAPα[34], and IL32[36] in fibroblasts derived from normal skin and MF tumors. Of the genes ana-…”

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confidence: 98%

Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma

2021

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“…Several markers have been used to confirm the presence of CAFs. These include α-smooth muscle actin (α-SMA) ( 23 ), tenascin-C ( 24 ), neuron glial antigen 2, platelet-derived growth factor receptor-alpha/beta (PDGFR-α or β), fibroblast activation protein (FAP) ( 25 ), CD90, matrix metalloproteinase 2 ( 26 ), and podoplanin ( 27 – 29 ). In addition, CAFs are also positive for mesenchymal markers such as vimentin, type I collagen, fibronectin, FSP-1/S100A4 ( 30 ), and prolyl-4-hydroxylase.…”

Section: Origin and Heterogeneity Of Cafsmentioning

confidence: 99%

Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Chen

Wei

et al. 2021

Front. Immunol.

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Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

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“…The reprogrammed microenvironment could facilitate the malignant phenotype of tumor cells, such as proliferation, invasion, migration, and pro-vasculogenic effects ( 16 ). Meanwhile, increasing evidence suggested that the disorganized microenvironment may contribute to tumor cells’ abilities to escape the effects of conventional treatments, such as chemotherapy, radiotherapy, and anti-vasculogenic therapy, as well as some classical molecular targeting therapies ( 17 – 19 ).…”

Section: Introductionmentioning

confidence: 99%

Re-Clustering and Profiling of Digestive System Tumors According to Microenvironment Components

Wang¹,

Guo²,

Chen³

et al. 2021

Front. Oncol.

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BackgroundImmunotherapy has become the most promising therapy in digestive system tumors besides conventional chemotherapy and radiotherapy. But only a few patients can benefit from different types of immunotherapies, such as immune checkpoint blockade (ICB). To identify these ICB-susceptible patients, methods are urgently needed to screen and profile subgroups of patients with different responsiveness to ICB.MethodsThis study carried out analysis on patients with digestive system tumors that were obtained from Cancer Genome Atlas (TCGA) cohorts. The analyses were mainly performed using GraphPad Prism 7 and R language.ResultsWe have quantified the microenvironmental components of eight digestive system tumor patients in TCGA cohorts and evaluated their clinical value. We re-clustered patients based on their microenvironment composition and divided these patients into six clusters. The differences between these six clusters were profiled, including survival conditions, enriched biological processes, genomic mutations, and microenvironment traits. Cluster 3 was the most immune-related cluster, exhibiting a high infiltration of non-tumor components and poor survival status, along with an inhibitory immune status, and we found that patients with high stromal score indicated a poor response in ICB cohort.ConclusionsOur research provides a new strategy based on the microenvironment components for the reclassification of digestive system tumors, which could provide guidance for prognosis judgment and treatment response prediction like ICB.

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Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4

Cited by 32 publications

References 48 publications

Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma

Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma

Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Re-Clustering and Profiling of Digestive System Tumors According to Microenvironment Components

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