Subject(s)
Immunotherapy , NF-kappa B , Ovarian Neoplasms/genetics , Ovarian Neoplasms/therapy , Cell Line, Tumor , Female , Humans , Transcription Factor RelAABSTRACT
The infiltration of immune cells is a hallmark of most forms of malignancy. It is well known that in Tumor Microenvironment (TME), monocytes undergo reprogramming process to differentiate into Tumor Associated Macrophages (TAMs) (M2 macrophages). Interestingly, this reprogramming process depends on signals provided by tumors. Hence, tumors from several tissues are infiltrated by functionally distinct TAMs populations. Tumor Protein p53(TP53) plays a role in the regulation or progression of DNA damage and repair through multiple mechanisms of the cell cycle, apoptosis, and genomic stability. Although, TP53 acts as a physiological break for M2 macrophages polarization; the potential regulatory function of TP53 in the infiltration of macrophages is still unknown. We used the Cancer Genomic Atlas (TCGA) clinical data from 10,009 samples across 30 types of cancer via the Tumor IMmune Estimation Tool (TIMER) (https://cistrome.shinyapps.io/timer/) to investigate whether TP53 status has an important clinical outcome on macrophages infiltration in different cancer types. Our analysis of TCGA showed that Ovarian Serous Cystadenocarcinoma (OV) patients with mutant TP53 had significantly higher macrophages infiltration than those with wild-type TP53 (P-value < 0.05) and poor prognosis associated. In contrast, Stomach Adenocarcinoma (STAD) patients with wild-type TP53 had considerably higher macrophages infiltration than those with mutant TP53 (P-value < 0.01) and poor clinical outcomes. Herein, our study sheds light on the novel clinical role of TP53 in macrophages infiltration in TME of OV and STAD patients. Furthermore, the modulation of TP53 and its co-regulators may serve as promising targets for OV and STAD patients.
Subject(s)
Adenocarcinoma/immunology , Cystadenocarcinoma, Serous/immunology , Genome/genetics , Ovarian Neoplasms/immunology , Stomach Neoplasms/immunology , Tumor Suppressor Protein p53/metabolism , Tumor-Associated Macrophages/immunology , Adenocarcinoma/genetics , Cell Movement , Cystadenocarcinoma, Serous/genetics , Cytokines/metabolism , Databases, Factual , Female , Humans , Male , Mutation/genetics , Ovarian Neoplasms/genetics , Stomach Neoplasms/genetics , Th2 Cells/immunology , Tumor Microenvironment , Tumor Suppressor Protein p53/geneticsSubject(s)
Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/pathology , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/physiology , Neoplastic Stem Cells/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Cell Differentiation/genetics , Cell Movement/genetics , Cell Proliferation/genetics , Cystadenocarcinoma, Serous/diagnosis , Cystadenocarcinoma, Serous/therapy , Doublecortin-Like Kinases , Female , Gene Expression , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Molecular Targeted Therapy , Neoplasm Staging , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/therapy , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolismABSTRACT
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC.
Subject(s)
GATA3 Transcription Factor/metabolism , Neoplasms, Cystic, Mucinous, and Serous/metabolism , Neoplasms, Cystic, Mucinous, and Serous/pathology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Tumor-Associated Macrophages/metabolism , Apoptosis/genetics , Cell Communication/genetics , Cell Line, Tumor , Cell Movement , Cell Polarity/genetics , Endometrial Neoplasms/pathology , Endothelial Cells/pathology , Epigenesis, Genetic , Epithelial-Mesenchymal Transition/genetics , Exosomes/metabolism , Exosomes/ultrastructure , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Genome, Human , Humans , Matrix Metalloproteinase 9/metabolism , Mutation/genetics , Neoplasm Grading , Neoplasm Proteins/metabolism , Neoplasms, Cystic, Mucinous, and Serous/genetics , Neovascularization, Pathologic/genetics , Ovarian Neoplasms/genetics , Phosphorylation , RNA Splice Sites/genetics , Tumor Microenvironment/genetics , Tumor Suppressor Protein p53/genetics , Tumor-Associated Macrophages/pathologyABSTRACT
In 2015, more than 1.6 million new cancer cases with 589,430 deaths were estimated over worldwide. Cancer is a complex disease with abnormal cell growth control which is hallmarked by chromosome misalignment and consequently genomic instability. Mitosis is a well-known target for chemotherapy as taxol and colchicines inhibit tumor cell division by inhibiting mitotic spindle plasticity. Accumulating evidence has revealed that the Centromere-associated Protein E (CENP-E) is expressed during mitosis and plays critical roles in inaccurate chromosome alignment. Thus, CENP-E might represent a druggable target for several solid tumors which do not have targeted therapy. Moreover, CENP-E appears during the mitotic phase of cell cycle and not implicates in the neuronal function. Hence, we will shed light on CENP-E as an emerging target for chemotherapy in clinical oncology and highlight challenges and excitement down the road.
