Cancer Res Treat.  2020 Oct;52(4):1273-1282. 10.4143/crt.2020.032.

Forkhead Box C1 (FOXC1) Expression in Stromal Cells within the Microenvironment of T and NK Cell Lymphomas: Association with Tumor Dormancy and Activation

• Nahm JH
• Yang WI
• Yoon SO

• KMID: 2507952
• DOI: http://doi.org/10.4143/crt.2020.032

Abstract

Purpose
Forkhead box C1 (FOXC1) is critical for maintaining bone marrow microenvironments during hematopoiesis, but its role in hematological malignancies remains obscure. Here, we investigated whether FOXC1 regulates tumor dormancy and activation in the microenvironments of T and natural killer (NK) cell lymphomas.
Materials and Methods
One hundred and twenty cases of T and NK cell lymphomas were included; the immunohistochemical expression of FOXC1 was investigated in stromal cells, and numbers of FOXC1⁺ stromal cells were counted. Furthermore, the expression of phosphorylated p38 (p-p38) and phosphorylated ERK1/2 (p-ERK1/2) in tumor cells was investigated using immunohistochemistry.
Results
FOXC1 was variably expressed in C-X-C motif chemokine 12–associated reticular stromal cells, histiocytes, (myo)fibroblasts, and endothelial cells. The phenotypes of cases were categorized as dormant (high p-p38/low p-ERK1/2; n=30, 25.0%), active (high p-ERK1/2/low p-p38; n=25, 20.8%), or intermediate (others; n=65, 54.2%). Lower FOXC1⁺ stromal cell infiltration was associated with the dormant phenotype, the precursor T lymphoblastic leukemia/lymphoma subtype, and inferior overall survival rates, whereas higher FOXC1⁺ stromal cell infiltration was associated with the active phenotype and favorable patient prognosis (p < 0.05 for all).
Conclusion
These results suggested that FOXC1⁺ stromal cells within the microenvironments of T and NK cell lymphomas might be related to tumor phenotypes.

Keyword

FOXC1; T and NK cell lymphomas; tumor microenvironment; stromal cells; dormancy; p38; ERK

Figure

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  Fig. 1. Representative features of the microenvironments of T and NK cell lymphomas (×400). Hematoxylin and eosin staining, and immunostaining for FOXC1, CXCL12, CD163, CD68 (PG-M1), SMA, CD34, and S100. FOXC1 was expressed in stromal cells, which were morphologically compatible with reticular spindle cells, histiocytes, activated macrophages, (myo)fibroblasts, and endothelial cells. NK, natural killer; FOXC1, forkhead box C1; SMA, smooth muscle actin.

• 

  Fig. 2. Phenotypes of tumor cells based on p-p38 and p-ERK1/2 expression. (A) Tumor cells with high p-ERK1/2 and low p-p38 were grouped into an active phenotype (n=25), those with high p-p38 and low p-ERK1/2 were grouped into a dormant phenotype (n=30), and the remaining cases were defined as an intermediate phenotype (n=65). (B) The active phenotype showed significantly higher FOXC1+ stromal cell infiltration into the tumor microenvironments than the dormant or intermediate phenotypes. p-p38, phosphorylated p38; p-ERK1/2, phosphorylated ERK1/2; FOXC1, forkhead box C1.

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  Fig. 3. Number of FOXC1+ stromal cells based on T and NK cell tumor subtype and anatomic site/organ of the tumors. (A) Precursor T lymphoblastic leukemia/lymphoma samples had significantly lower numbers of FOXC1+ stromal cells than mature T or NK cell lymphoma samples. (B) Head and neck sites were associated with higher FOXC1+ stromal cell infiltration than did other sites/organs. FOXC1, forkhead box C1; NK, natural killer; PTCL, NOS, peripheral T cell lymphoma, not otherwise specified; NKTL, extranodal natural killer/T cell lymphoma; AITL, angioimmunoblastic T cell lymphoma; ALK, anaplastic lymphoma kinase; ALCL, anaplastic large-cell lymphoma; T-LBL, precursor T lymphoblastic leukemia/lymphoma; GI, gastrointestinal.

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  Fig. 4. Comparison of the mRNA levels of FOXC1, p38 MAPKs (MAPK11, MAPK14, MAPK12, and MAPK13), ERK MAPKs (MAPK1/ERK2 and MAPK3/ERK1), and DUSP1 (MAPK phosphatase 1, MKP-1; regulator of MAPK phosphorylation) in acute myeloid leukemia (The Cancer Genome Atlas Network, PanCancer Atlas; n=165). Note that the expression of p38 MAPKs was not high in cases showing high FOXC1 expression. FOXC1, forkhead box C1; MAPK, mitogen-activated protein kinase.

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  Fig. 5. Kaplan-Meier analyses for overall survival of T and NK cell lymphoma patients. Lower FOXC1+ stromal cell infiltration (A), age > 60 years (B), lymph nodes as the primary tumor site (C), higher Ann-Arbor stage (≥ III) (D), and higher IPI score (≥ 3) (E) were significantly related to poor overall survival. (F) Dormant, active, or intermediate tumor phenotypes showed no significant association with overall survival. Survival analyses were performed for cases with available survival and clinicopathological data. NK, natural killer; FOXC1, forkhead box C1; IPI, International Prognostic Index.

Reference

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