The possible interaction between periostin expressed by cancer stroma and tumor‐associated macrophages in developing mycosis fungoides

Abstract

Mycosis fungoides (MF) starts as an indolent disease, progresses from a patch stage to confluent plaques and ultimately develops skin tumors. Tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment in MF. The purpose of this study was to elucidate the involvement of TAMs in the lesional skin of different stages of MF. First, we immunohistologically examined the percentage of CD163+ macrophages and CD206+ cells, as well as the levels of periostin and IL-4 in cancer stroma. The percentage of CD206+ cells increased in parallel with tumor progression, while there was no significant difference in the percentage of CD163+ cells. Periostin was prominent in the stromal area at the patch and plaque stages but decreased at the tumor stage. In contrast, IL-4 was prominently stained at both plaque and tumor stages. To further elucidate the molecular mechanisms of the effects of these stromal factors on TAMs, we examined their effects on mRNA expression in monocyte-derived macrophages in vitro. Based on microarray analysis and gene ontology, we examined a series of chemokines and MMPs whose expression was strongly connected with periostin stimulation. The DNA microarray results were verified in M2 macrophages using real-time PCR. We further examined the mRNA expression of these chemokines and MMPs in the presence of periostin and IL-4 to simulate the advanced stages of MF and validated their protein expression by ELISA. Our present report suggests possible roles of periostin on TAMs in establishing the tumor microenvironment in MF.

Tumor-associated M2 macrophages in mycosis fungoides acquire immunomodulatory function by interferon alpha and interferon gamma

“…Most infiltrating cells express CXCR3, which binds to CXCL9, CXCL10 and CXCL11 at the early stages of MF, whereas the tumor cells express CCR4, which binds to CCL17 and CCL22 at the advanced stage of MF [1,3]. In addition, as we previously reported, the cancer stroma differs with each tumor stage [4]. These reports suggest that the tumor microenvironment of MF polarizes from Th1-to Th2-dominant in parallel with the tumor progression.…”

“…In cutaneous T-cell lymphoma (CTCL), macrophage-related chemokines and angiogenic factors produced by TAMs have crucial roles in tumor formation in the lesional skin of MF [8,9]. In addition, we have also reported that the stromal factor of MF, periostin, could stimulate macrophages to produce chemokines that affect the formation of MF [4]. In another report, IFN-b modulates the profiles of chemokines from TAMs to recruit the tumor-specific effector T cells in murine melanoma [10].…”

“…CD14 + monocytes (2 Â 10 5 /ml) were cultured in complete medium containing 100 ng/ml of recombinant human M-CSF for 5 days, as previously reported [4,11,12]. On the fifth day, the monocyte-derived M2 macrophages (M2Mf) were treated with IL-4 (20 ng/ml) together with IFN-a2a (20 ng/ml) or IFN-g (20 ng/ ml).…”

Receptor activator of nuclear factor kappa‐B ligand (RANKL)/RANK signaling promotes cancer‐related inflammation through M2 macrophages

“…We then stimulated these macrophages with or without 100 ng/ml of sRANKL for 6 h and examined gene expression using a cDNA microarray (4). Based on gene set enrichment analysis of the microarray results, we focused on chemokine genes and cytokine genes that were modified by sRANKL treatment.…”

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

“…For example, previous studies by our group and others have demonstrated alterations in NK-cell signaling because of the presence of suppressive myeloid cells such as myeloid-derived suppressor cells and tumor-associated macrophages in cancer patients, 26 and both populations have been reported among CTCL patients. [27][28][29] Additional checkpoint inhibitors, such as PD-1, CTLA-4, TIGIT, and TIM-3 may also play a role in decreasing NK-cell function in patients, because previous studies demonstrated that these inhibitors may be increased in the presence of IL-15.…”