Browsing by Author "Mohamed, Mona Mostafa"

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Differential gene expression of Fresh Tissue and Patient-Derived Explants' Matricellular Proteins Augment Inflammatory Breast Cancer Metastasis: The Possible Role of IL-6 and MCP-1.
(Dove Medical Press Ltd., 2023-01) Tarek, Alshaimaa; Mohamed, Hossam Taha; El-Sharkawy, Aya Ali; El-Sayed, Shrouk Khalaf; Hirshon, Jon Mark; Woodward, Wendy A; El-Shinawi, Mohamed; Mohamed, Mona Mostafa
Background Matricellular proteins comprising matrisome and adhesome are responsible for structure integrity and interactions between cells in the tumour microenvironment of breast cancer. Changes in the gene expression of matrisome and adhesome augment metastasis. Since inflammatory breast cancer (IBC) is characterized by high metastatic behavior. Herein we compared the gene expression profile of matrisome and adhesome in non-IBC and IBC in fresh tissue and ex-vivo patients derived explants (PDEs), we also compared the secretory inflammatory mediators of PDEs in non-IBC and IBC to identify secretory cytokines participate in cross-talk between cells via interactions with matrisome and adhisome. Methods Fifty patients (31 non-IBC; 19 IBC) were enrolled in the present study. To test their validation in clinical studies, PDEs were cultured as an ex-vivo model. Gene expression and cytokine array were used to identify candidate genes and cytokines contributing to metastasis in the examined fresh tissues and PDEs. Bioinformatics analysis was applied on identified differentially expressed genes (DEGs) using GeneMANIA and Metascape gene annotation and analysis resource to identify pathways involved in IBC metastasis. Results Normal and cancer fresh tissues and PDEs of IBC were characterized by overexpression of CDH1 and MMP14 and downregulation of CTNNA1 and TIMP1 compared to non-IBC. The secretome of IBC cancer PDEs is characterized by significantly high expression of interleukin 6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared to non-IBC. Conclusion Genes expressed by adhisome and matrisome play a significant role in IBC metastasis and should be considered novel target therapy.
Editorial: Inflammatory tumor microenvironment: role of cytokines and virokines in breast cancer progression and metastasis
(Frontiers Media SA, 2024-06) Mohamed, Hossam Taha; El-Shinawi, Mohamed; Mohamed, Mona Mostafa
Various factors contributing to breast cancer progression and metastasis (Feng et al., 2018; Park et al., 2022). One of these factors is the presence of inflammatory tumor microenvironment (TME), which composed of cellular components (e.g., cancer cells, immune cells, endothelial cells, fibroblasts, mast cells) and non-cellular components (e.g., extracellular matrix proteins, cytokines, chemokines, signal molecules), and it differs significantly from the normal tissue microenvironment in terms of low vascular density, hypoxia, weak acidity, and reducibility (Zarrilli et al., 2020). Breast cancer cells control the function of TME components via the expression of cytokines that can increase selfproliferation, growth, and treatment resistance in an autocrine form, and encourage recruitment, activation, and differentiation of other cells in the TME in a paracrine approach as IL-6, IL-8, and even VEGF (Malla and Kiran, 2022; Nengroo et al., 2022; Habanjar et al., 2023).
IL-8 secreted by tumor associated macrophages contribute to lapatinib resistance in HER2-positive locally advanced breast cancer via activation of Src/STAT3/ERK1/2-mediated EGFR signaling
(Elsevier, 03/02/2021) Ahmed, Shaza; Taha Mohamed, Hossam; El-Husseiny, Noura; El Mahdy, Manal M; Safwat, Gehan; Diab, Ayman A; El-Sherif, Ahmed A; El-Shinawi, Mohamed; Mohamed, Mona Mostafa
Locally advanced breast cancer (LABC) is an aggressive disease characterized by late clinical presentation, large tumor size, treatment resistance and low survival rate. Expression of EGFR/HER2 and activation of intracellular tyrosine kinase domains in LABC are associated with poor prognosis. Thus, target therapies such as the anti-receptor tyrosine kinases lapatinib drug have been more developed in the past decade. The response to lapatinib involves the inhibition of RTKs and subsequently signaling molecules such as Src/STAT3/Erk1/2 known also to be activated by the cytokines in the tumor microenvironment (TME). The aim of the present study is to identify the major cytokine that might contribute to lapatinib resistance in EGFR+/HER2+ LABC patients. Indeed, tumor associated macrophages (TAMs) are the main source of cytokines in the TME. Herein, we isolated TAMs from LABC during modified radical mastectomy (MRM). Cytokine profile of TAMs revealed that IL-8 is the most prominent highly secreted cytokine by TAMs of LABC patients. Using in-vitro cell culture model we showed that recombinant IL-8 (50 and 100 ng/mL) at different time intervals interfere with lapatinib action via activation of Src/EGFR and signaling molecules known to be inhibited during treatment. We proposed that to improve LABC patients' response to lapatinib treatment it is preferred to use combined therapy that neutralize or block the action of IL-8.
Inflammatory Breast Cancer: The Secretome of HCMV+ Tumor-Associated Macrophages Enhances Proliferation, Invasion, Colony Formation, and Expression of Cancer Stem Cell Markers
(Frontiers Media S.A., 2022-06) Mohamed, Hossam Taha; El-Sharkawy, Aya Ali; El-Shinawi, Mohamed; Schneider, Robert J; Mohamed, Mona Mostafa
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-AMPKa, 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-AMPKa, p-PRAS40, and p- SAPK/JNK intracellular signaling molecules in IBC cells. UV
Synchrotron Fourier-Transform Infrared Microspectroscopy: Characterization of In Vitro Polarized Tumor-associated Macrophages Stimulated by The Secretome of Inflammatory and Non-Inflammatory Breast Cancer cells
(Elsevier, 2022-09) Mohamed, Hossam Taha; Kamel, Gihan; El-Husseiny, Noura; El-Sharkawy, Aliya; El-Sherif, Ahmed A.; El-Shinawi, Mohamed; Mohamed, Mona Mostafa
ct: Studies suggested that the pathogenesis of inflammatory breast cancer (IBC) is related to inflammatory manifestations accompanied by specific cellular and molecular mechanisms in the IBC tumor microenvironment (TME). IBC is characterized by significantly higher infiltration of tumor-associated macrophages (TAMs) that contribute to its metastatic process via secreting many cytokines such as TNF, IL-6, IL-8, and IL-10 that enhance invasion and angiogenesis. Thus, there is a need to first understand how IBC-TME modulates the polarization of TAMs to better understand the role of TAMs in IBC. Herein, we used gene expression signature and Synchrotron Fourier-Transform Infrared Microspectroscopy (SR- µFTIR) to study the molecular and biochemical changes, respectively of in vitro polarized TAMs stimulated by the secretome of IBC and non-IBC cells. The gene expression signature showed significant differences in the macrophage‟s polarization-related genes between stimulated TAMs. FTIR spectra showed absorption bands in the region of 1700- 1500 cm-1 attributed to the amide I (ν(C=O), & νAS (C-N), δ (N-H), and amide II ν(C-N), δ (N-H) proteins bands. Moreover, three peaks of different intensities and areas were detected in the lipid region of the vCH2 and vCH3 stretching modes positioned within the 3000 - 2800 cm-1 range. The PCA analysis for the second derivative spectra of the amide regions discriminates between stimulated IBC and non-IBC TAMs. This study showed that IBC and non-IBC TMEs differentially modulate the polarization of TAMs and SR-µFTIR can determine these biochemical changes which will help to better understand the potential role of TAMs in IBC.