Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700‑8525, Japan.
Int J Oncol. 2022 Jun;60(6). doi: 10.3892/ijo.2022.5368. Epub 2022 May 6.
Tumor‑associated macrophages (TAMs) are linked to the progression of numerous types of cancer. However, the effects of the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC), particularly the cancer stroma on TAMs, remains to be elucidated. In the present study, the effects of verrucous SCC‑associated stromal cells (VSCC‑SCs), SCC‑associated stromal cells (SCC‑SCs) and human dermal fibroblasts (HDFs) on the differentiation, proliferation and migration of macrophages was assayed using Giemsa staining, and immunofluorescence, MTS and Transwell (migration) assays, respectively. The combined results suggested that both VSCC‑SCs and SCC‑SCs promoted the differentiation of macrophages into M2 type TAMs, as well as the proliferation and migration of macrophages following crosstalk with HSC‑3 cells . Moreover, the SCC‑SCs exerted a more prominent effect on TAMs than the VSCC‑SCs. Immunohistochemical staining was used to examine the expression of CD34, CD45, CD11b and CD163 to assay the effects of VSCC‑SCs, SCC‑SCs and HDFs on microvessel density (MVD) and the infiltration of CD45(+) monocytes, CD11b(+) TAMs and CD163(+) M2 type macrophages. The results suggested that both VSCC‑SCs and SCC‑SCs promoted MVD and the infiltration of CD45(+) monocytes, CD11b(+) TAMs and CD163(+) M2 type TAMs into the TME of OSCC following crosstalk with HSC‑3 cells . The SCC‑SCs exerted a more prominent promoting effect than the VSCC‑SCs. Finally, the potential genes underlying the differential effects of VSCC‑SCs and SCC‑SCs on the infiltration of TAMs were investigated using microarray analysis. The results revealed that interleukin 1β, bone morphogenetic protein 4, interleukin 6 and C‑X‑C motif chemokine ligand 12 had great potential to mediate the differential effects of VSCC‑SCs and SCC‑SCs on TAM infiltration. On the whole, the findings presented herein, demonstrate that both VSCC‑SCs and SCC‑SCs promote the infiltration of TAMs into the TME of OSCC following crosstalk with HSC‑3 cells; the SCC‑SCs were found to exert a more prominent promoting effect. This may represent a potential regulatory mechanism for the infiltration of TAMs into the TME of OSCC.
肿瘤相关巨噬细胞（TAMs）与多种类型癌症的进展有关。然而，口腔鳞状细胞癌（OSCC）的肿瘤微环境（TME），特别是癌症基质对 TAMs 的影响，仍有待阐明。在本研究中，通过吉姆萨染色、免疫荧光、MTS 和 Transwell（迁移）试验分别检测了疣状 SCC 相关基质细胞（VSCC-SCs）、SCC 相关基质细胞（SCC-SCs）和人真皮成纤维细胞（HDFs）对巨噬细胞分化、增殖和迁移的影响。联合结果表明，VSCC-SCs 和 SCC-SCs 均促进巨噬细胞向 M2 型 TAMs 分化，并促进与 HSC-3 细胞共培养后的巨噬细胞增殖和迁移。此外，SCC-SCs 对 TAMs 的影响比 VSCC-SCs 更显著。免疫组织化学染色检测 CD34、CD45、CD11b 和 CD163 的表达，以检测 VSCC-SCs、SCC-SCs 和 HDFs 对微血管密度（MVD）和 CD45（+）单核细胞、CD11b（+）TAMs 和 CD163（+）M2 型巨噬细胞浸润的影响。结果表明，VSCC-SCs 和 SCC-SCs 均促进了 OSCC 的 TME 中 MVD 以及 CD45（+）单核细胞、CD11b（+）TAMs 和 CD163（+）M2 型 TAMs 的浸润，与 HSC-3 细胞共培养后。SCC-SCs 的促进作用比 VSCC-SCs 更显著。最后，通过微阵列分析研究了 VSCC-SCs 和 SCC-SCs 对 TAM 浸润的差异作用的潜在基因。结果表明，白细胞介素 1β、骨形态发生蛋白 4、白细胞介素 6 和 C-X-C 基序趋化因子配体 12 很可能介导 VSCC-SCs 和 SCC-SCs 对 TAM 浸润的差异作用。总的来说，本研究结果表明，VSCC-SCs 和 SCC-SCs 均促进了与 HSC-3 细胞共培养后 OSCC 的 TME 中 TAM 的浸润；SCC-SCs 的促进作用更为显著。这可能代表了 TAMs 浸润 OSCC 的 TME 的潜在调节机制。
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