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Cancer-Associated Fibroblasts Play an Important Role in Early-Stage Mycosis Fungoides

  • Chalid Assaf
    Correspondence
    Correspondence: Chalid Assaf, Department of Dermatology and Venerology, HELIOS Klinikum Krefeld, Lutherplatz 40, 47805 Krefeld, Germany.
    Affiliations
    Department of Dermatology and Venerolgy, HELIOS Klinikum Krefeld, Krefeld, Germany

    Department of Dermatology and Allergy, Skin Cancer Center Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany
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      Research in cutaneous T-cell lymphoma has widened from the malignant T cell itself to the tumor microenvironment. In this issue of the Journal of Investigative Dermatology, Aronovich et al. (2020) report the presence of cancer-associated fibroblasts (CAFs) in mycosis fungoides (MFs). They show that CAFs are abundant in early-stage MF and that they differ from normal fibroblasts. Moreover, CAFs are described to promote MF by increasing the motility and chemoresistance of malignant T cells. Thus, targeting CAFs in MF may be of therapeutic value.
      • Cancer-associated fibroblasts (CAFs) are abundant in early-stage mycosis fungoides (MFs) and may modulate the tumor environment.
      • CAFs promote the malignant T cells in MF by increasing their motility.
      • CAFs also play a role in drug resistance in MF by increasing the chemoresistance of the tumor cells.
      In recent decades, the focus on cancer research has extended from the malignant tumor cells themselves to the tumor microenvironment (TME) and the complicated interactions that occur between the stroma and the tumor cells. This concept was described in 1889 as the seed and soil hypothesis by Stephen Paget who suggested that elements of the stroma were important for tumor development. Paget proposed that metastasis is not due to random events but rather that some tumor cells (the seeds) grow preferentially in selected organs (the soil) and that metastases only appear when the appropriate seed was implanted in suitable soil (
      • Langley R.R.
      • Fidler I.J.
      The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs.
      ). This hypothesis has been confirmed by an extensive body of experimental research and clinical data with a corresponding dramatic increase in our understanding of the crosstalk that occurs between malignant cells and their organ microenvironment on the molecular, cellular, and systemic levels. Many components of the TME, including tumor-associated macrophages, tumor endothelial cells, and dendritic cells, as well as humoral factors, such as chemokines, have been described (
      • Langley R.R.
      • Fidler I.J.
      The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs.
      ). Recently, cancer-associated fibroblasts (CAFs), as components of the TME, have been demonstrated to play critical roles in tumorigenesis by facilitating tumor growth, angiogenesis, stromal remodeling, and resistance to drug therapy (
      • Kalluri R.
      The biology and function of fibroblasts in cancer.
      ).
      In cutaneous T-cell lymphoma (CTCL), the TME has been shown to play a decisive role in the pathogenesis of the disease. The growth and viability of CTCL cells are partly dependent on contact with immature dendritic cells, tumor-associated macrophages, and mast cells (
      • Assaf C.
      • Hwang S.T.
      Mac attack: macrophages as key drivers of cutaneous T-cell lymphoma pathogenesis.
      ;
      • Fujii K.
      New therapies and immunological findings in cutaneous T-cell lymphoma.
      ). It has also been demonstrated that fibroblasts in the affected skin of patients with advanced CTCL promote a T helper (Th)2‒dominant microenvironment by augmenting Th2 and attenuating Th1 immune responses (
      • Miyagaki T.
      • Sugaya M.
      • Fujita H.
      • Ohmatsu H.
      • Kakinuma T.
      • Kadono T.
      • et al.
      Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma.
      ). It seems that the malignant T cells in CTCL also shape their TME, thereby supporting disease progression. However, the precise role of CAFs in CTCL is still elusive.
      In this issue of the Journal of Investigating Dermatology,
      • Aronovich A.
      • Moyal L.
      • Gorovitz B.
      • Amitay-Laish I.
      • Naveh H.P.
      • Forer Y.
      • et al.
      Cancer-associated fibroblasts in mycosis fungoides promote tumor cell migration and drug resistance through CXCL12/CXCR4.
      report that CAFs exist in mycosis fungoides (MFs) (Figure 1a), the most common type of cutaneous lymphoma, and characterize their features and interactions with the tumor cells in the early stage of MF. These results are significant because they provide further evidence for a potential link between TME and CTCL progression as well as a rationale for targeting the CAF-mediated TME as an adjuvant treatment strategy in CTCL.
      Figure thumbnail gr1
      Figure 1CAFs in early-stage MF. (a) The clinical impression of early-stage (patch-stage) MF. (b) Representative histology (Giemsa, ×100) of early-stage MF with epidermotropic atypical lymphocytes and directly beneath (arrows) the thickening of collagen bundles in the superficial dermis—papillary dermal fibrosis. (Bar = 200 μm). (c) scheme of tumor remodeling by CAFs (left) and crosstalk of CAFs with the malignant T cells (left). The patient gave consent for the publication of his photo. CAF, cancer-associated fibroblast; MMP2, matrix metalloproteinase 2.
      The authors show in this study that CAFs are abundant in early-stage MF and that they differ from normal fibroblasts, exhibiting increased expression of genes responsible for collagen and extracellular matrix (EM) proteins such as collagen XI and matrix metalloproteinase 2 (MMP2), respectively. Activation of the collagen XI gene is a prerequisite for collagen production, and MMP2 as a proteolytic enzyme is responsible for cleaving EM, for example, such as collagen procession and, by this, promoting the EM remodeling. These activities could be the cause or contribute to the extended collagen deposition leading to a morphological correlate—the papillary dermal fibrosis (Figure 1b)—that is a useful diagnostic clue in the early stage of MF (
      • Guitart J.
      • Kennedy J.
      • Ronan S.
      • Chmiel J.S.
      • Hsiegh Y.C.
      • Variakojis D.
      Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting.
      ).
      Functionally,
      • Aronovich A.
      • Moyal L.
      • Gorovitz B.
      • Amitay-Laish I.
      • Naveh H.P.
      • Forer Y.
      • et al.
      Cancer-associated fibroblasts in mycosis fungoides promote tumor cell migration and drug resistance through CXCL12/CXCR4.
      demonstrate that CAFs enhance the cell motility of MF tumor cells and protect the tumor cells from doxorubicin-induced cell death by the upregulation of protumor factors through the activation of the CXCL12-CXCR4 axis. These results reveal a potential therapeutic target because the inhibition of this axis leads to the opposite effect of reduced tumor cell motility and enhanced apoptosis induced by doxorubicin. These data indicate that CAFs play an essential role not only in regulating tumor cell proliferation and motility but also in drug resistance in MF (Figure 1c).
      Although this study represents an important advance, important questions remain open. For example, mechanisms of conversion of normal fibroblasts into CAFs and for signaling between activated CAF and tumor cells and also with immune cells have not been elucidated. However, on the basis of the results of
      • Aronovich A.
      • Moyal L.
      • Gorovitz B.
      • Amitay-Laish I.
      • Naveh H.P.
      • Forer Y.
      • et al.
      Cancer-associated fibroblasts in mycosis fungoides promote tumor cell migration and drug resistance through CXCL12/CXCR4.
      , CAF targeting in MF may become an interesting option. Several preclinical strategies that target specific actions or subpopulations of CAFs, for example, by targeting their receptors as CD10 or GPR77 or CAF-specific microRNA (
      • Santana-Viera L.
      • Ibba M.L.
      • Rotoli D.
      • Catuogno S.
      • Esposito C.L.
      Emerging therapeutic RNAs for the targeting of cancer associated fibroblasts.
      ;
      • Su S.
      • Chen J.
      • Yao H.
      • Liu J.
      • Yu S.
      • Lao L.
      • et al.
      CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness.
      ), are being actively studied. Another promising approach involves the restoration of the chemosensitivity in tumors through the re-education of CAFs toward normal by epigenetic regulation (
      • Tommelein J.
      • De Vlieghere E.
      • Verset L.
      • Melsens E.
      • Leenders J.
      • Descamps B.
      • et al.
      Radiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF1R activation.
      ). Because
      • Aronovich A.
      • Moyal L.
      • Gorovitz B.
      • Amitay-Laish I.
      • Naveh H.P.
      • Forer Y.
      • et al.
      Cancer-associated fibroblasts in mycosis fungoides promote tumor cell migration and drug resistance through CXCL12/CXCR4.
      show that CAFs play a major role in the early stage of MF, inhibition of CAF number or activity could prevent progression to the advanced, often challenging stage of this malignancy.

      ORCID

      Conflict of Interest

      The author states no conflict of interest.

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      Linked Article

      • Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4
        Journal of Investigative DermatologyVol. 141Issue 3
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          Cancer cells are known to reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) to act as tumor supporters. The presence and role of CAFs in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, are unknown. This study sought to characterize CAFs in MF and their cross talk with the lymphoma cells using primary fibroblast cultures from punch biopsies of patients with early-stage MF and healthy subjects. MF cultures yielded significantly increased levels of FAPα, a CAF marker, and CAF-associated genes and proteins: CXCL12 (ligand of CXCR4 expressed on MF cells), collagen XI, and matrix metalloproteinase 2.
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