scholarly journals Matrisome Deregulation in Ovarian Cancer Metastasis

2020 ◽  
Vol 3 ◽  
Author(s):  
Jessica Tedrow ◽  
Ji Wang ◽  
Anirban Mitra
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Tumor Development ◽  
3D Culture ◽  
Progression Free Survival ◽  
Metastatic Tumor ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Tissue Modulus

Background and Hypothesis: Over 75% of ovarian cancer (OC) patients present with metastasis upon initial diagnosis. Since most are treated for metastatic disease, it is crucial that developing therapies target metastasis. Our analysis of OC transcriptomic changes revealed key changes in the matrisome. Matrisome genes are associated with tissue modulus and disease progression, yet comprehensive understanding of many of their contributions to OC is lacking. We hypothesize that matrisomal OC genes will have clear impacts on clinical outcomes.   Project Methods: Differentially expressed genes (DEG) in 11 paired OC primary tumors and metastases were identified using RNA-seq analysis. The DEG were compared with data from high-grade serous ovarian cancer (HGSOC) cells seeded on an organotypic 3D culture model of omentum. The overlapping genes are deregulated during early metastasis and remain relevant in advanced metastasis in OC patients. Kaplan-Meier Plots were generated to identify gene relationships with progression-free survival (PFS) and overall survival (OS).   Results: 845 genes between metastases and primary tumors and 1,182 genes between early and advanced metastatic colonization were differentially expressed; 144 genes were shared. These 144 genes were compared with matrisome proteins differentially expressed between malignant and non-malignant HGSOC cell populations. 28 genes correlated with tissue modulus, 19 with disease score, and 17 with both. Of the 30 matrisome genes correlating with either, 21 decreased PFS and 24 decreased OS.   Conclusion and Potential Impact: We have identified a matrisome signature sustained throughout metastatic tumor development. Many of these genes’ mechanisms contributing to OC metastasis and therapeutic relevance have yet to be determined. In addition to influencing cell-cell communications, mechanotransduction, and metastasis progression, the altered matrisome can affect drug delivery to tumors. Further studies may guide understanding of pathways in matrisome alteration during cancer progression and reveal future targets for chemotherapy or combination immunotherapies. 

scholarly journals Identification and Functional Validation of Differentially Expressed Micrornas in Ascites-derived Ovarian Cancer Cells Compared With Primary Tumour Tissue

2020 ◽  
Author(s):  
Yahui Jiang ◽  
Tianjiao Lyu ◽  
Hua Liu ◽  
Lifei Shen ◽  
Yiwen Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Primary Tumour ◽  
Malignant Ascites ◽  
Differentially Expressed ◽  
Tumour Tissue ◽  
Ovarian Cancer Cells ◽  
Hub Genes ◽  
Mirnas Expression

Abstract Purpose: Ovarian cancer, manifested by malignant ascites, is the most lethal gynaecological cancer. Suspended ascites-derived spheroids may contribute to ovarian cancer metastasis. MicroRNAs (miRNAs) are also associated with ovarian cancer metastasis. Here, we aimed to investigate the differentially expressed miRNAs (DE-miRNAs) in ascites-derived spheroids compared with primary tumour tissue, which may regulate ovarian cancer metastasis.Methods: The DE-miRNAs between ovarian cancer primary tumour tissues and ascites-derived spheroids were identified by GEO2R screening in dataset GSE65819. We used MiRTarBase and STRING to predict the target hub genes of DE-miRNAs and WebGestalt to perform functional analysis of hub genes. ALGGEN PROMO and TransmiR v2.0 were used to predict the common transcription factors (TFs) that potentially regulate DE-miRNAs expression. The observed differences in DE-miRNAs expression were validated with human ovarian cancer samples and ovarian cancer cell lines using PCR. The functions of DE-miRNAs on ovarian cancer progression were verified by transwell and angiogenesis assays.Results: Through bioinformatics screening and experimental validation, miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p were identified as being significantly downregulated in ascites-derived spheroids compared with primary tumour tissues. In addition, TFAP2A was identified as a potentially common upstream TF regulating the expression of the abovementioned DE-miRNAs. The overexpression of miR-199a-3p, miR-199b-3p, miR-199a-5p could inhibit ovarian cancer invasion, and the overexpression of miR-145-5p could inhibit angiogenesis.Conclusion: The downregulated expression of miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p in ascites-derived spheroids plays a key role in promoting ovarian cancer progression, which may represent novel molecules for targeted therapy for ovarian cancer.

scholarly journals Transcriptome Profiling Reveals Matrisome Alteration as a Key Feature of Ovarian Cancer Progression

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1513 ◽  
Author(s):  
Sumegha Mitra ◽  
Kartikeya Tiwari ◽  
Ram Podicheti ◽  
Taruni Pandhiri ◽  
Douglas B. Rusch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cancer Progression ◽  
3D Culture ◽  
Ovarian Cancer Cells ◽  
Fallopian Tubes ◽  
Rna Seq ◽  
Primary Tumors ◽  
Metastatic Colonization ◽  
Culture Model

Background: Ovarian cancer is the most lethal gynecologic malignancy. There is a lack of comprehensive investigation of disease initiation and progression, including gene expression changes during early metastatic colonization. Methods: RNA-sequencing (RNA-seq) was done with matched primary tumors and fallopian tubes (n = 8 pairs) as well as matched metastatic and primary tumors (n = 11 pairs) from ovarian cancer patients. Since these are end point analyses, it was combined with RNA-seq using high-grade serous ovarian cancer cells seeded on an organotypic three-dimensional (3D) culture model of the omentum, mimicking early metastasis. This comprehensive approach revealed key changes in gene expression occurring in ovarian cancer initiation and metastasis, including early metastatic colonization. Results: 2987 genes were significantly deregulated in primary tumors compared to fallopian tubes, 845 genes were differentially expressed in metastasis compared to primary tumors and 304 genes were common to both. An assessment of patient metastasis and 3D omental culture model of early metastatic colonization revealed 144 common genes that were altered during early colonization and remain deregulated even in the fully developed metastasis. Deregulation of the matrisome was a key process in early and late metastasis. Conclusion: These findings will help in understanding the key pathways involved in ovarian cancer progression and eventually targeting those pathways for therapeutic interventions.

scholarly journals Identification and Functional Validation of Differentially Expressed microRNAs in Ascites-derived Ovarian Cancer Cells Compared With Primary Tumour Tissue

2020 ◽  
Author(s):  
Yahui Jiang ◽  
Tianjiao Lyu ◽  
Hua Liu ◽  
Lifei Shen ◽  
Yiwen Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Primary Tumour ◽  
Malignant Ascites ◽  
Differentially Expressed ◽  
Tumour Tissue ◽  
Ovarian Cancer Cells ◽  
Hub Genes ◽  
Mirnas Expression

Abstract Purpose: Ovarian cancer, manifested by malignant ascites, is the most lethal gynaecological cancer. Suspended ascites-derived spheroids may contribute to ovarian cancer metastasis. MicroRNAs (miRNAs) are also associated with ovarian cancer metastasis. Here, we aimed to investigate the differentially expressed miRNAs (DE-miRNAs) in ascites-derived spheroids compared with primary tumour tissue, which may regulate ovarian cancer metastasis. Methods: The DE-miRNAs between ovarian cancer primary tumour tissues and ascites-derived spheroids were identified by GEO2R screening in dataset GSE65819. We used MiRTarBase, TargetScanHuman7.2 and STRING to predict the target hub genes of DE-miRNAs and DAVID to perform functional analysis of hub genes. ALGGEN PROMO and TransmiR v2.0 were used to predict the common transcription factors (TFs) that potentially regulate DE-miRNAs expression. The observed differences in DE-miRNAs expression were validated with human ovarian cancer samples and ovarian cancer cell lines using PCR. The functions of DE-miRNAs on ovarian cancer progression were verified by transwell and angiogenesis assays. Results: Through bioinformatics screening and experimental validation, miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p were identified as being significantly downregulated in ascites-derived spheroids compared with primary tumour tissues. In addition, TFAP2A was identified as a potentially common upstream TF regulating the expression of the abovementioned DE-miRNAs. The overexpression of miR-199a-3p, miR-199b-3p, miR-199a-5p could inhibit ovarian cancer invasion, and the overexpression of miR-145-5p could inhibit angiogenesis. Conclusion: The downregulated expression of miR-199a-3p, miR-199b-3p, miR-199a-5p, miR-126-3p and miR-145-5p in ascites-derived spheroids plays a key role in promoting ovarian cancer progression, which may represent novel molecules for targeted therapy for ovarian cancer.

scholarly journals Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Tetsu Hayashida ◽  
Hiromitsu Jinno ◽  
Yuko Kitagawa ◽  
Masaki Kitajima
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Tumor ◽  
Breast Cancer Metastasis ◽  
Cell Junctions ◽  
Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

scholarly journals Differential expression of SLIT and NTRK-like family member 3 in human epithelial ovarian cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Family Member ◽  
Fallopian Tube ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
High Grade ◽  
Primary Tumors ◽  
Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published and public microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding SLIT and NTRK-like family member 3, SLITRK3, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. SLITRK3 expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. SLITRK3 expression correlated with progression-free survival in patients with ovarian cancer. These data indicate that expression of SLITRK3 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. SLITRK3 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

scholarly journals Differential expression of sarcospan in human epithelial ovarian cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Fallopian Tube ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Gene Expression Profiles ◽  
Progression Free Survival ◽  
High Grade ◽  
Primary Tumors ◽  
Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding sarcospan, SSPN, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. SSPN expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. SSPN expression correlated with progression-free survival in patients with ovarian cancer. These data indicate that expression of SSPN is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. SSPN may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

scholarly journals Differential expression of phosphodiesterase 5A in human epithelial ovarian cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Fallopian Tube ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Gene Expression Profiles ◽  
Progression Free Survival ◽  
High Grade ◽  
Primary Tumors ◽  
Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding phosphodiesterase 5A, PDE5A, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. PDE5A expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. PDE5A expression correlated with progression-free survival in patients with p53 mutant ovarian cancer. These data indicate that expression of PDE5A is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. PDE5A may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

scholarly journals Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 24 ◽  
Author(s):  
Chin-Jui Wu ◽  
Vignesh Sundararajan ◽  
Bor-Ching Sheu ◽  
Ruby Yun-Ju Huang ◽  
Lin-Hung Wei
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Progression ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Microenvironmental Factors ◽  
Therapeutic Opportunity ◽  
Molecular Therapeutic

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.

scholarly journals Bromodomain-Containing Protein 4: A Dynamic Regulator of Breast Cancer Metastasis through Modulation of the Extracellular Matrix

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jude Alsarraj ◽  
Kent W. Hunter
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Susceptibility Gene ◽  
Breast Cancer Metastasis ◽  
Primary Tumors ◽  
Inherited Susceptibility ◽  
Complex Process ◽  
Host Genetic

Metastasis is an extremely complex process that accounts for most cancer-related deaths. Malignant primary tumors can be removed surgically, but the cells that migrate, invade, and proliferate at distant organs are often the cells that prove most difficult to target therapeutically. There is growing evidence that host factors outside of the primary tumors are of major importance in the development of metastasis. Recently, we have shown that the bromodomain-containing protein 4 or bromodomain 4 (Brd4) functions as an inherited susceptibility gene for breast cancer progression and metastasis. In this paper, we will discuss that host genetic background on which a tumor arises can significantly alter the biology of the subsequent metastatic disease, and we will focus on the role ofBrd4in regulating metastasis susceptibility.

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