Inflammatory Breast Cancer: The Secretome of HCMV+ Tumor-Associated Macrophages Enhances Proliferation, Invasion, Colony Formation, and Expression of Cancer Stem Cell Markers

Abstract

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 in vitro 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.

Influence of Macrophages on Vascular Invasion of Inflammatory Breast Cancer Emboli Measured Using an In Vitro Microfluidic Multi-Cellular Platform

“…Macrophages have been implicated in the phenotype and progression of IBC in many studies [22,25,53,54]. Here, we examined the effect of macrophages on vascular development and matrix structure using a 3D microfluidic platform and found that macrophages, particularly IL4 and IL13 stimulated macrophages, enhance sprouting observed from endothelial cells cultured with IBC cells, enhance collagen porosity, and promote tumor emboli intravasation into the vessel.…”

“…Macrophages have been implicated in the phenotype and progression of IBC in many studies [22,25,53,54]. Here, we examined the effect of macrophages on vascular…”

The role of oncolytic virotherapy and viral oncogenes in the cancer stem cells: a review of virus in cancer stem cells

“…Moreover, the phosphorylation of intracellular signaling molecules such as p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK was induced in SUM149 cells upon exposure to the secretome of HCMV-positive tumor-associated macrophages. The findings of this study indicate that the secretion profile of TAMs infected with HCMV leads to heightened proliferative, invasive, colony-forming, and BCSC traits through the phosphorylation of intracellular signaling molecules such as p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK in cells of inflammatory breast cancer [ 71 ].…”

“…The LMP2A-NFB route was used to activate the capacity to form spheres, and EBVaGC might target this pathway as a potential therapeutic target [ 65 ] EBV Nasopharyngeal carcinoma EBV, LMP1, which is linked to human cancers, including nasopharyngeal carcinoma (NPC), promotes tumor cell invasion, metastasis, and EMT. LMP1 allows NPC to develop CSC-like traits by turning on the mTORC1 and mTORC2 pathways [ 64 ] HCMV Glioblastoma (GBM) The phenotypic flexibility that HCMV infection causes in GBM cells to boost GCSC characteristics may increase the tumor’s aggressiveness [ 68 ] HCMV Breast cancer HCMV + TAMs promote proliferation, invasion, colony formation, and BCSC characteristics in inflammatory breast cancer cells via promoting the phosphorylation of p-STAT3, p-AMPK, p-PRAS40, and p-SAPK/JNK intracellular signaling molecules [ 71 ] ADV GBM NEAT1 knockdown reduced the stemness of ADV-induced GSCs. Finally, HMGB1, a DAMP that activates TLR signaling, increased the expression of stemness markers in glioma cells [ 77 ] …”

Editorial: Inflammatory tumor microenvironment: role of cytokines and virokines in breast cancer progression and metastasis

“…2015; Mohamed et al, 2022). There are viral proteins can mimic and interfere with cytokines associated with carcinogenesis in the host cell, these proteins called Virokines (Smith and Kotwal, 2001).…”