Coalition of Oct4A and β1 integrins in facilitating metastasis in ovarian cancer
- Samardzija, Chantel, Luwor, Rodney, Quinn, Michael, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Samardzija, Chantel , Luwor, Rodney , Quinn, Michael , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2016
- Type: Text , Journal article
- Relation: BMC Cancer Vol. 16, no. 1 (2016), p. 1-16
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- Description: Background: Ovarian cancer is a metastatic disease and one of the leading causes of gynaecology malignancy-related deaths in women. Cancer stem cells (CSCs) are key contributors of cancer metastasis and relapse. Integrins are a family of cell surface receptors which allow interactions between cells and their surrounding microenvironment and play a fundamental role in promoting metastasis. This study investigates the molecular mechanism which associates CSCs and integrins in ovarian cancer metastasis. Methods: The expression of Oct4A in high-grade serous ovarian tumors and normal ovaries was determined by immunofluorescence analysis. The functional role of Oct4A was evaluated by generating stable knockdown (KD) of Oct4A clones in an established ovarian cancer cell line HEY using shRNA-mediated silencing. The expression of integrins in cell lines was evaluated by flow cytometry. Spheroid forming ability, adhesion and the activities of matrix metalloproteinases 9/2 (MMP-9/2) was measured by in vitro functional assays and gelatin zymography. These observations were further validated in in vivo mouse models using Balb/c nu/nu mice. Results: We report significantly elevated expression of Oct4A in high-grade serous ovarian tumors compared to normal ovarian tissues. The expression of Oct4A in ovarian cancer cell lines correlated with their CSC-related sphere forming abilities. The suppression of Oct4A in HEY cells resulted in a significant diminution of integrin β1 expression and associated α5 and α2 subunits compared to vector control cells. This was associated with a reduced adhesive ability on collagen and fibronectin and decreased secretion of pro-MMP2 in Oct4A KD cells compared to vector control cells. In vivo, Oct4A knock down (KD) cells produced tumors which were significantly smaller in size and weight compared to tumors derived from vector control cells. Immunohistochemical analyses of Oct4A KD tumor xenografts demonstrated a significant loss of cytokeratin 7 (CK7), Glut-1 as well as CD34 and CD31 compared to vector control cell-derived xenografts. Conclusion: The expression of Oct4A may be crucial to promote and sustain integrin-mediated extracellular matrix (ECM) remodeling requisite for tumor metastasis in ovarian cancer patients. © 2016 The Author(s).
- Authors: Samardzija, Chantel , Luwor, Rodney , Quinn, Michael , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2016
- Type: Text , Journal article
- Relation: BMC Cancer Vol. 16, no. 1 (2016), p. 1-16
- Full Text:
- Reviewed:
- Description: Background: Ovarian cancer is a metastatic disease and one of the leading causes of gynaecology malignancy-related deaths in women. Cancer stem cells (CSCs) are key contributors of cancer metastasis and relapse. Integrins are a family of cell surface receptors which allow interactions between cells and their surrounding microenvironment and play a fundamental role in promoting metastasis. This study investigates the molecular mechanism which associates CSCs and integrins in ovarian cancer metastasis. Methods: The expression of Oct4A in high-grade serous ovarian tumors and normal ovaries was determined by immunofluorescence analysis. The functional role of Oct4A was evaluated by generating stable knockdown (KD) of Oct4A clones in an established ovarian cancer cell line HEY using shRNA-mediated silencing. The expression of integrins in cell lines was evaluated by flow cytometry. Spheroid forming ability, adhesion and the activities of matrix metalloproteinases 9/2 (MMP-9/2) was measured by in vitro functional assays and gelatin zymography. These observations were further validated in in vivo mouse models using Balb/c nu/nu mice. Results: We report significantly elevated expression of Oct4A in high-grade serous ovarian tumors compared to normal ovarian tissues. The expression of Oct4A in ovarian cancer cell lines correlated with their CSC-related sphere forming abilities. The suppression of Oct4A in HEY cells resulted in a significant diminution of integrin β1 expression and associated α5 and α2 subunits compared to vector control cells. This was associated with a reduced adhesive ability on collagen and fibronectin and decreased secretion of pro-MMP2 in Oct4A KD cells compared to vector control cells. In vivo, Oct4A knock down (KD) cells produced tumors which were significantly smaller in size and weight compared to tumors derived from vector control cells. Immunohistochemical analyses of Oct4A KD tumor xenografts demonstrated a significant loss of cytokeratin 7 (CK7), Glut-1 as well as CD34 and CD31 compared to vector control cell-derived xenografts. Conclusion: The expression of Oct4A may be crucial to promote and sustain integrin-mediated extracellular matrix (ECM) remodeling requisite for tumor metastasis in ovarian cancer patients. © 2016 The Author(s).
Knockdown of stem cell regulator Oct4A in ovarian cancer reveals cellular reprogramming associated with key regulators of cytoskeleton-extracellular matrix remodelling
- Samardzija, Chantel, Greening, David, Escalona, Ruth, Chen, Maoshan, Bilandzic, Maree, Luwor, Rodney, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Samardzija, Chantel , Greening, David , Escalona, Ruth , Chen, Maoshan , Bilandzic, Maree , Luwor, Rodney , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. (2017), p. 1-18
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- Reviewed:
- Description: Oct4A is a master regulator of self-renewal and pluripotency in embryonic stem cells. It is a well-established marker for cancer stem cell (CSC) in malignancies. Recently, using a loss of function studies, we have demonstrated key roles for Oct4A in tumor cell survival, metastasis and chemoresistance in in vitro and in vivo models of ovarian cancer. In an effort to understand the regulatory role of Oct4A in tumor biology, we employed the use of an ovarian cancer shRNA Oct4A knockdown cell line (HEY Oct4A KD) and a global mass spectrometry (MS)-based proteomic analysis to investigate novel biological targets of Oct4A in HEY samples (cell lysates, secretomes and mouse tumor xenografts). Based on significant differential expression, pathway and protein network analyses, and comprehensive literature search we identified key proteins involved with biologically relevant functions of Oct4A in tumor biology. Across all preparations of HEY Oct4A KD samples significant alterations in protein networks associated with cytoskeleton, extracellular matrix (ECM), proliferation, adhesion, metabolism, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and drug resistance was observed. This comprehensive proteomics study for the first time presents the Oct4A associated proteome and expands our understanding on the biological role of this stem cell regulator in carcinomas. © 2017 The Author(s).
- Authors: Samardzija, Chantel , Greening, David , Escalona, Ruth , Chen, Maoshan , Bilandzic, Maree , Luwor, Rodney , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. (2017), p. 1-18
- Full Text:
- Reviewed:
- Description: Oct4A is a master regulator of self-renewal and pluripotency in embryonic stem cells. It is a well-established marker for cancer stem cell (CSC) in malignancies. Recently, using a loss of function studies, we have demonstrated key roles for Oct4A in tumor cell survival, metastasis and chemoresistance in in vitro and in vivo models of ovarian cancer. In an effort to understand the regulatory role of Oct4A in tumor biology, we employed the use of an ovarian cancer shRNA Oct4A knockdown cell line (HEY Oct4A KD) and a global mass spectrometry (MS)-based proteomic analysis to investigate novel biological targets of Oct4A in HEY samples (cell lysates, secretomes and mouse tumor xenografts). Based on significant differential expression, pathway and protein network analyses, and comprehensive literature search we identified key proteins involved with biologically relevant functions of Oct4A in tumor biology. Across all preparations of HEY Oct4A KD samples significant alterations in protein networks associated with cytoskeleton, extracellular matrix (ECM), proliferation, adhesion, metabolism, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and drug resistance was observed. This comprehensive proteomics study for the first time presents the Oct4A associated proteome and expands our understanding on the biological role of this stem cell regulator in carcinomas. © 2017 The Author(s).
Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer
- Chan, Emily, Luwor, Rodney, Burns, Christopher, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Chan, Emily , Luwor, Rodney , Burns, Christopher , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2018
- Type: Text , Journal article
- Relation: Oncotarget Vol. 9, no. 24 (2018), p. 16599-16618
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- Description: Despite a good initial response to front-line chemotherapy, majority of the ovarian cancer patients relapse with consecutive phases of recurrences; and nearly 60% die within 5 years due to the development of a chemoresistant disease. This study investigated whether inhibition of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway by momelotinib is sufficient in suppressing tumor burden and prolonging the disease-free survival period in a mouse model of ovarian cancer. We demonstrate that paclitaxel treatment enhanced JAK2/STAT3 activation which resulted in the enrichment of cancer stem cell (CSC)- like phenotype in the surviving ovarian cancer cells in vitro and in in vivo mouse xenografts. Combined treatment with paclitaxel and momelotinib inhibited paclitaxelinduced JAK2/STAT3 activation and CSC-like development in mice xenografts, and consequently reduced the tumor burden significantly greater than that achieved by paclitaxel-treatment alone. However, robust recurrent tumor growth with enhanced JAK2/STAT3 activation and CSC-like phenotype was observed in all mice groups after termination of treatments, but was delayed significantly in the paclitaxel and momelotinib treated group compared to other treatment groups. Daily oral gavage of momelotinib after termination of paclitaxel treatment showed sustained inhibition of tumor growth and a prolonged disease-free survival period in 50% of the mice. The other 50% of mice that developed tumors with ongoing momelotinib treatment also showed significantly increased survival benefit and a smaller tumor burden. These preliminary findings may have a profound clinical impact in developing an effective momelotinib-based 'maintenance-therapy' in ovarian cancer patients' postchemotherapy treatment. © Chan et al.
- Authors: Chan, Emily , Luwor, Rodney , Burns, Christopher , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2018
- Type: Text , Journal article
- Relation: Oncotarget Vol. 9, no. 24 (2018), p. 16599-16618
- Full Text:
- Reviewed:
- Description: Despite a good initial response to front-line chemotherapy, majority of the ovarian cancer patients relapse with consecutive phases of recurrences; and nearly 60% die within 5 years due to the development of a chemoresistant disease. This study investigated whether inhibition of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway by momelotinib is sufficient in suppressing tumor burden and prolonging the disease-free survival period in a mouse model of ovarian cancer. We demonstrate that paclitaxel treatment enhanced JAK2/STAT3 activation which resulted in the enrichment of cancer stem cell (CSC)- like phenotype in the surviving ovarian cancer cells in vitro and in in vivo mouse xenografts. Combined treatment with paclitaxel and momelotinib inhibited paclitaxelinduced JAK2/STAT3 activation and CSC-like development in mice xenografts, and consequently reduced the tumor burden significantly greater than that achieved by paclitaxel-treatment alone. However, robust recurrent tumor growth with enhanced JAK2/STAT3 activation and CSC-like phenotype was observed in all mice groups after termination of treatments, but was delayed significantly in the paclitaxel and momelotinib treated group compared to other treatment groups. Daily oral gavage of momelotinib after termination of paclitaxel treatment showed sustained inhibition of tumor growth and a prolonged disease-free survival period in 50% of the mice. The other 50% of mice that developed tumors with ongoing momelotinib treatment also showed significantly increased survival benefit and a smaller tumor burden. These preliminary findings may have a profound clinical impact in developing an effective momelotinib-based 'maintenance-therapy' in ovarian cancer patients' postchemotherapy treatment. © Chan et al.
Ovarian cancer, cancer stem cells and current treatment strategies : a potential role of magmas in the current treatment methods
- Ahmed, Nuzhat, Kadife, Elif, Raza, Ali, Short, Mary, Jubinsky, Paul, Kannourakis, George
- Authors: Ahmed, Nuzhat , Kadife, Elif , Raza, Ali , Short, Mary , Jubinsky, Paul , Kannourakis, George
- Date: 2020
- Type: Text , Journal article , Review
- Relation: Cells Vol. 9, no. 3 (Mar 2020), p. 35
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- Reviewed:
- Description: Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease.
- Authors: Ahmed, Nuzhat , Kadife, Elif , Raza, Ali , Short, Mary , Jubinsky, Paul , Kannourakis, George
- Date: 2020
- Type: Text , Journal article , Review
- Relation: Cells Vol. 9, no. 3 (Mar 2020), p. 35
- Full Text:
- Reviewed:
- Description: Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease.
Paclitaxel-induced Src activation is inhibited by dasatinib treatment, independently of cancer stem cell properties, in a mouse model of ovarian cancer
- Kadife, Elif, Chan, Emily, Luwor, Rodney, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Kadife, Elif , Chan, Emily , Luwor, Rodney , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2019
- Type: Text , Journal article
- Relation: Cancers Vol. 11, no. 2 (2019), p. 1-24
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- Description: Approximately seventy percent of ovarian cancer patients succumb to the disease within the first 5 years of diagnosis, even after successful surgery and effective chemotherapy treatment. A small subset of chemotherapy resistant cancer stem cells (CSCs) cause relapse of ovarian cancers. This study investigated the association between paclitaxel-mediated Src activation (p-Src) and CSC populations in driving ovarian cancer progression. We demonstrate that patients with high-stage serous ovarian carcinomas have significantly elevated levels of p-Src, compared to patient with low-stage and benign ovarian tumours. Additionally, p-Src was significantly enhanced in ascites-derived tumour cells obtained from recurrent patients, compared to chemonaïve patients. Paclitaxel treatment increased Src activation in ovarian cancer cells, causing enrichment of CSC marker expression in the surviving cells in vitro and in xenografts of nude mice. Dasatinib in combination with paclitaxel significantly suppressed p-Src in ovarian cancer cell lines and xenografts but had no effect on the expression of CSC markers. However, combination of paclitaxel and Dasatinib showed lower trend in invasion in liver and pancreas, compared to paclitaxel-only treatment. The tumours treated with combination therapy also had significantly lower infiltration of mononuclear cells. Robust recurrent tumour growth was observed in all mice groups after termination of treatments. The above results suggest that Dasatinib-mediated inhibition of p-Src may not be crucial for paclitaxel-induced CSC-mediated recurrence in ovarian cancer.
- Authors: Kadife, Elif , Chan, Emily , Luwor, Rodney , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2019
- Type: Text , Journal article
- Relation: Cancers Vol. 11, no. 2 (2019), p. 1-24
- Full Text:
- Reviewed:
- Description: Approximately seventy percent of ovarian cancer patients succumb to the disease within the first 5 years of diagnosis, even after successful surgery and effective chemotherapy treatment. A small subset of chemotherapy resistant cancer stem cells (CSCs) cause relapse of ovarian cancers. This study investigated the association between paclitaxel-mediated Src activation (p-Src) and CSC populations in driving ovarian cancer progression. We demonstrate that patients with high-stage serous ovarian carcinomas have significantly elevated levels of p-Src, compared to patient with low-stage and benign ovarian tumours. Additionally, p-Src was significantly enhanced in ascites-derived tumour cells obtained from recurrent patients, compared to chemonaïve patients. Paclitaxel treatment increased Src activation in ovarian cancer cells, causing enrichment of CSC marker expression in the surviving cells in vitro and in xenografts of nude mice. Dasatinib in combination with paclitaxel significantly suppressed p-Src in ovarian cancer cell lines and xenografts but had no effect on the expression of CSC markers. However, combination of paclitaxel and Dasatinib showed lower trend in invasion in liver and pancreas, compared to paclitaxel-only treatment. The tumours treated with combination therapy also had significantly lower infiltration of mononuclear cells. Robust recurrent tumour growth was observed in all mice groups after termination of treatments. The above results suggest that Dasatinib-mediated inhibition of p-Src may not be crucial for paclitaxel-induced CSC-mediated recurrence in ovarian cancer.
- Zhai, Jiali, Luwor, Rodney, Ahmed, Nuzhat, Escalona, Ruth, Tan, Fiona, Fong, Celesta, Ratcliffe, Julian, Scoble, Judith, Drummond, Calum, Tran, Nhiem
- Authors: Zhai, Jiali , Luwor, Rodney , Ahmed, Nuzhat , Escalona, Ruth , Tan, Fiona , Fong, Celesta , Ratcliffe, Julian , Scoble, Judith , Drummond, Calum , Tran, Nhiem
- Date: 2018
- Type: Text , Journal article
- Relation: ACS Applied Materials & Interfaces Vol. 10, no. 30 (2018), p. 25174-25185
- Full Text: false
- Reviewed:
- Description: Chemotherapy using cytotoxic agents, such as paclitaxel (PTX), is one of the most effective treatments for advanced ovarian cancer. However, due to nonspecific targeting of the drug and the presence of toxic solvents required for dissolving PTX prior to injection, there are several serious side effects associated with this treatment. In this study, we explored self-assembled lipid-based nanoparticles as PTX carriers, which were able to improve its antitumour efficacy against ovarian cancer. The nanoparticles were also functionalized with epidermal growth factor receptor (EGFR) antibody fragments to explore the benefit of tumor active targeting. The formulated bicontinuous cubic- and sponge-phase nanoparticles, which were stabilized by Pluronic F127 and a lipid poly(ethylene glycol) stabilizer, showed a high capacity of PTX loading. These PTX-loaded nanoparticles also showed significantly higher cytotoxicity than a free drug formulation against HEY ovarian cancer cell lines in vitro. More importantly, the nanoparticle-based PTX treatments, with or without EGFR targeting, reduced the tumor burden by 50% compared to PTX or nondrug control in an ovarian cancer mouse xenograft model. In addition, the PTX-loaded nanoparticles were able to extend the survival of the treatment groups by up to 10 days compared to groups receiving free PTX or nondrug control. This proof-of-concept study has demonstrated the potential of these self-assembled lipid nanomaterials as effective drug delivery nanocarriers for poorly soluble chemotherapeutics, such as PTX.
The many facets of metzincins and their endogenous inhibitors : Perspectives on ovarian cancer progression
- Escalona, Ruth, Chan, Emily, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Escalona, Ruth , Chan, Emily , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2018
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 19, no. 2 (2018), p. 1-33
- Full Text:
- Reviewed:
- Description: Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
- Authors: Escalona, Ruth , Chan, Emily , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2018
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 19, no. 2 (2018), p. 1-33
- Full Text:
- Reviewed:
- Description: Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells : Perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells
- Ahmed, Nuzhat, Escalona, Ruth, Leung, Dilys, Chan, Emily, Kannourakis, George
- Authors: Ahmed, Nuzhat , Escalona, Ruth , Leung, Dilys , Chan, Emily , Kannourakis, George
- Date: 2018
- Type: Text , Journal article , Review
- Relation: Seminars in Cancer Biology Vol. 53, no. (2018), p. 265-281
- Full Text:
- Reviewed:
- Description: Cancer stem cells (CSCs) are a sub-population of tumour cells, which are responsible to drive tumour growth, metastasis and therapy resistance. It has recently been proposed that enhanced glucose metabolism and immune evasion by tumour cells are linked, and are modulated by the changing tumour microenvironment (TME) that creates a competition for nutrient consumption between tumour and different sub-types of cells attracted to the TME. To facilitate efficient nutrient distribution, oncogene-induced inflammatory milieu in the tumours facilitate adaptive metabolic changes in the surrounding non-malignant cells to secrete metabolites that are used as alternative nutrient sources by the tumours to sustain its increasing energy needs for growth and anabolic functions. This scenario also affects CSCs residing at the primary or metastatic niches. This review summarises recent advances in our understanding of the metabolic phenotypes of cancer cells and CSCs and how these processes are affected by the TME. We also discuss how the evolving TME modulates tumour cells and CSCs in cancer progression. Using previously described proteomic and genomic platforms, ovarian cancer cell lines and a mouse xenograft model we highlight the existence of metabolic and immune regulatory signatures in chemoresistant ovarian CSCs, and discuss how these processes may affect recurrence in ovarian tumours. We propose that progress in cancer control and eradication may depend not only on the elimination of highly chemoresistant CSCs, but also in designing novel strategies which would intervene with the tumour-promoting TME factors.
- Authors: Ahmed, Nuzhat , Escalona, Ruth , Leung, Dilys , Chan, Emily , Kannourakis, George
- Date: 2018
- Type: Text , Journal article , Review
- Relation: Seminars in Cancer Biology Vol. 53, no. (2018), p. 265-281
- Full Text:
- Reviewed:
- Description: Cancer stem cells (CSCs) are a sub-population of tumour cells, which are responsible to drive tumour growth, metastasis and therapy resistance. It has recently been proposed that enhanced glucose metabolism and immune evasion by tumour cells are linked, and are modulated by the changing tumour microenvironment (TME) that creates a competition for nutrient consumption between tumour and different sub-types of cells attracted to the TME. To facilitate efficient nutrient distribution, oncogene-induced inflammatory milieu in the tumours facilitate adaptive metabolic changes in the surrounding non-malignant cells to secrete metabolites that are used as alternative nutrient sources by the tumours to sustain its increasing energy needs for growth and anabolic functions. This scenario also affects CSCs residing at the primary or metastatic niches. This review summarises recent advances in our understanding of the metabolic phenotypes of cancer cells and CSCs and how these processes are affected by the TME. We also discuss how the evolving TME modulates tumour cells and CSCs in cancer progression. Using previously described proteomic and genomic platforms, ovarian cancer cell lines and a mouse xenograft model we highlight the existence of metabolic and immune regulatory signatures in chemoresistant ovarian CSCs, and discuss how these processes may affect recurrence in ovarian tumours. We propose that progress in cancer control and eradication may depend not only on the elimination of highly chemoresistant CSCs, but also in designing novel strategies which would intervene with the tumour-promoting TME factors.
Unique proteome signature of post-chemotherapy ovarian cancer ascites-derived tumor cells
- Ahmed, Nuzhat, Greening, David, Samardzija, Chantel, Escalona, Ruth, Chen, Maoshan, Findlay, Jock, Kannourakis, George
- Authors: Ahmed, Nuzhat , Greening, David , Samardzija, Chantel , Escalona, Ruth , Chen, Maoshan , Findlay, Jock , Kannourakis, George
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-13
- Full Text:
- Reviewed:
- Description: Eighty % of ovarian cancer patients diagnosed at an advanced-stage have complete remission after initial surgery and chemotherapy. However, most patients die within <5 years due to episodes of recurrences resulting from the growth of residual chemoresistant cells. In an effort to identify mechanisms associated with chemoresistance and recurrence, we compared the expression of proteins in ascites-derived tumor cells isolated from advanced-stage ovarian cancer patients obtained at diagnosis (chemonaive, CN) and after chemotherapy treatments (chemoresistant/at recurrence, CR) by using in-depth, high-resolution label-free quantitative proteomic profiling. A total of 2,999 proteins were identified. Using a stringent selection criterion to define only significantly differentially expressed proteins, we report identification of 353 proteins. There were significant differences in proteins encoding for immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of metabolic pathways, DNA repair mechanisms and energy metabolism pathways in CR tumor cells. In conclusion, this is the first proteomics study to comprehensively analyze ascites-derived tumor cells from CN and CR ovarian cancer patients.
- Authors: Ahmed, Nuzhat , Greening, David , Samardzija, Chantel , Escalona, Ruth , Chen, Maoshan , Findlay, Jock , Kannourakis, George
- Date: 2016
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 6, no. (2016), p. 1-13
- Full Text:
- Reviewed:
- Description: Eighty % of ovarian cancer patients diagnosed at an advanced-stage have complete remission after initial surgery and chemotherapy. However, most patients die within <5 years due to episodes of recurrences resulting from the growth of residual chemoresistant cells. In an effort to identify mechanisms associated with chemoresistance and recurrence, we compared the expression of proteins in ascites-derived tumor cells isolated from advanced-stage ovarian cancer patients obtained at diagnosis (chemonaive, CN) and after chemotherapy treatments (chemoresistant/at recurrence, CR) by using in-depth, high-resolution label-free quantitative proteomic profiling. A total of 2,999 proteins were identified. Using a stringent selection criterion to define only significantly differentially expressed proteins, we report identification of 353 proteins. There were significant differences in proteins encoding for immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of metabolic pathways, DNA repair mechanisms and energy metabolism pathways in CR tumor cells. In conclusion, this is the first proteomics study to comprehensively analyze ascites-derived tumor cells from CN and CR ovarian cancer patients.
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