Mohamed Hossam Taha, El-Sharkawy Aya Ali, El-Shinawi Mohamed, Schneider Robert J, Mohamed Mona Mostafa
Zoology Department, Faculty of Science, Cairo University, Giza, Egypt.
Faculty of Biotechnology, October University for Modern Sciences and Arts, Giza, Egypt.
Front Oncol. 2022 Jun 30;12:899622. doi: 10.3389/fonc.2022.899622. eCollection 2022.
Inflammatory breast cancer (IBC) is a highly aggressive phenotype of breast cancer that is characterized by a high incidence early metastasis. We previously reported a significant association of human cytomegalovirus (HCMV) DNA in the carcinoma tissues of IBC patients but not in the adjacent normal tissues. HCMV-infected macrophages serve as "mobile vectors" for spreading and disseminating virus to different organs, and IBC cancer tissues are highly infiltrated by tumor-associated macrophages (TAMs) that enhance IBC progression and promote breast cancer stem cell (BCSC)-like properties. Therefore, there is a need to understand the role of HCMV-infected TAMs in IBC progression. The present study aimed to test the effect of the secretome (cytokines and secreted factors) of TAMs derived from HCMV monocytes isolated from IBC specimens on the proliferation, invasion, and BCSC abundance when tested on the IBC cell line SUM149. HCMV monocytes were isolated from IBC patients during modified radical mastectomy surgery and tested for polarization into TAMs using the secretome of SUM149 cells. MTT, clonogenic, invasion, real-time PCR arrays, PathScan Intracellular Signaling array, and cytokine arrays were used to characterize the secretome of HCMV TAMs for their effect on the progression of SUM149 cells. The results showed that the secretome of HCMV TAMs expressed high levels of IL-6, IL-8, and MCP-1 cytokines compared to HCMV TAMs. In addition, the secretome of HCMV TAMs induced the proliferation, invasion, colony formation, and expression of BCSC-related genes in SUM149 cells compared to mock untreated cells. In addition, the secretome of HCMV TAMs activated the phosphorylation of intracellular signaling molecules p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK in SUM149 cells. In conclusion, this study shows that the secretome of HCMV TAMs enhances the proliferation, invasion, colony formation, and BCSC properties by activating the phosphorylation of p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK intracellular signaling molecules in IBC cells.
炎性乳腺癌（IBC）是一种侵袭性很强的乳腺癌表型，其特点是早期转移发生率高。我们之前报道过，IBC患者癌组织中存在人巨细胞病毒（HCMV）DNA，而相邻正常组织中则没有。HCMV感染的巨噬细胞作为“移动载体”，将病毒传播和扩散到不同器官，IBC癌组织中肿瘤相关巨噬细胞（TAM）高度浸润，这些细胞会促进IBC进展并促进乳腺癌干细胞（BCSC）样特性。因此，有必要了解HCMV感染的TAM在IBC进展中的作用。本研究旨在测试从IBC标本中分离出的HCMV单核细胞来源的TAM分泌组（细胞因子和分泌因子）对IBC细胞系SUM149的增殖、侵袭和BCSC丰度的影响。在改良根治性乳房切除术期间从IBC患者中分离出HCMV单核细胞，并使用SUM149细胞的分泌组测试其向TAM的极化。使用MTT、克隆形成、侵袭、实时PCR阵列、PathScan细胞内信号传导阵列和细胞因子阵列来表征HCMV TAM分泌组对SUM149细胞进展的影响。结果显示，与HCMV TAM相比，HCMV TAM分泌组表达高水平的IL-6、IL-8和MCP-1细胞因子。此外，与未处理的对照细胞相比，HCMV TAM分泌组诱导SUM149细胞增殖、侵袭、集落形成以及BCSC相关基因的表达。此外，HCMV TAM分泌组激活SUM149细胞中细胞内信号分子p-STAT3、p-AMPKα、p-PRAS40和p-SAPK/JNK的磷酸化。总之，本研究表明，HCMV TAM分泌组通过激活IBC细胞中p-STAT3,p-AMPKα,p-PRAS40和p-SAPK/JNK细胞内信号分子的磷酸化来增强增殖、侵袭、集落形成和BCSC特性。
