Crosstalk between immune checkpoint modulators, metabolic reprogramming and cellular plasticity in triple-negative breast cancer
- Poddar, Arpita, Rao, Sushma, Prithviraj, Prithviraj, Kannourakis, George, Jayachandran, Aparna
- Authors: Poddar, Arpita , Rao, Sushma , Prithviraj, Prithviraj , Kannourakis, George , Jayachandran, Aparna
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Current Oncology Vol. 29, no. 10 (2022), p. 6847-6863
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- Description: Breast cancer is one of the major causes of mortality in women worldwide. Accounting for 15–20% of all breast cancer diagnoses, the triple-negative breast cancer (TNBC) subtype presents with an aggressive clinical course, heightened metastatic potential and the poorest short-term prognosis. TNBC does not respond to hormonal therapy, only partially responds to radio- and chemotherapy, and has limited targeted therapy options, thus underlining the critical need for better therapeutic treatments. Although immunotherapy based on immune checkpoint inhibition is emerging as a promising treatment option for TNBC patients, activation of cellular plasticity programs such as metabolic reprogramming (MR) and epithelial-to-mesenchymal transition (EMT) causes immunotherapy to fail. In this report, we review the role of MR and EMT in immune checkpoint dysregulation in TNBCs and specifically shed light on development of novel combination treatment modalities for this challenging disease. We highlight the clinical relevance of crosstalk between MR, EMT, and immune checkpoints in TNBCs. © 2022 by the authors.
- Authors: Poddar, Arpita , Rao, Sushma , Prithviraj, Prithviraj , Kannourakis, George , Jayachandran, Aparna
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Current Oncology Vol. 29, no. 10 (2022), p. 6847-6863
- Full Text:
- Reviewed:
- Description: Breast cancer is one of the major causes of mortality in women worldwide. Accounting for 15–20% of all breast cancer diagnoses, the triple-negative breast cancer (TNBC) subtype presents with an aggressive clinical course, heightened metastatic potential and the poorest short-term prognosis. TNBC does not respond to hormonal therapy, only partially responds to radio- and chemotherapy, and has limited targeted therapy options, thus underlining the critical need for better therapeutic treatments. Although immunotherapy based on immune checkpoint inhibition is emerging as a promising treatment option for TNBC patients, activation of cellular plasticity programs such as metabolic reprogramming (MR) and epithelial-to-mesenchymal transition (EMT) causes immunotherapy to fail. In this report, we review the role of MR and EMT in immune checkpoint dysregulation in TNBCs and specifically shed light on development of novel combination treatment modalities for this challenging disease. We highlight the clinical relevance of crosstalk between MR, EMT, and immune checkpoints in TNBCs. © 2022 by the authors.
Precision medicine : an optimal approach to patient care in renal cell carcinoma
- Sharma, Revati, Kannourakis, George, Prithviraj, Prashanth, Ahmed, Nuzhat
- Authors: Sharma, Revati , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Frontiers in Medicine Vol. 9, no. (2022), p.
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- Description: Renal cell cancer (RCC) is a heterogeneous tumor that shows both intra- and inter-heterogeneity. Heterogeneity is displayed not only in different patients but also among RCC cells in the same tumor, which makes treatment difficult because of varying degrees of responses generated in RCC heterogeneous tumor cells even with targeted treatment. In that context, precision medicine (PM), in terms of individualized treatment catered for a specific patient or groups of patients, can shift the paradigm of treatment in the clinical management of RCC. Recent progress in the biochemical, molecular, and histological characteristics of RCC has thrown light on many deregulated pathways involved in the pathogenesis of RCC. As PM-based therapies are rapidly evolving and few are already in current clinical practice in oncology, one can expect that PM will expand its way toward the robust treatment of patients with RCC. This article provides a comprehensive background on recent strategies and breakthroughs of PM in oncology and provides an overview of the potential applicability of PM in RCC. The article also highlights the drawbacks of PM and provides a holistic approach that goes beyond the involvement of clinicians and encompasses appropriate legislative and administrative care imparted by the healthcare system and insurance providers. It is anticipated that combined efforts from all sectors involved will make PM accessible to RCC and other patients with cancer, making a tremendous positive leap on individualized treatment strategies. This will subsequently enhance the quality of life of patients. Copyright © 2022 Sharma, Kannourakis, Prithviraj and Ahmed.
- Authors: Sharma, Revati , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Frontiers in Medicine Vol. 9, no. (2022), p.
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- Description: Renal cell cancer (RCC) is a heterogeneous tumor that shows both intra- and inter-heterogeneity. Heterogeneity is displayed not only in different patients but also among RCC cells in the same tumor, which makes treatment difficult because of varying degrees of responses generated in RCC heterogeneous tumor cells even with targeted treatment. In that context, precision medicine (PM), in terms of individualized treatment catered for a specific patient or groups of patients, can shift the paradigm of treatment in the clinical management of RCC. Recent progress in the biochemical, molecular, and histological characteristics of RCC has thrown light on many deregulated pathways involved in the pathogenesis of RCC. As PM-based therapies are rapidly evolving and few are already in current clinical practice in oncology, one can expect that PM will expand its way toward the robust treatment of patients with RCC. This article provides a comprehensive background on recent strategies and breakthroughs of PM in oncology and provides an overview of the potential applicability of PM in RCC. The article also highlights the drawbacks of PM and provides a holistic approach that goes beyond the involvement of clinicians and encompasses appropriate legislative and administrative care imparted by the healthcare system and insurance providers. It is anticipated that combined efforts from all sectors involved will make PM accessible to RCC and other patients with cancer, making a tremendous positive leap on individualized treatment strategies. This will subsequently enhance the quality of life of patients. Copyright © 2022 Sharma, Kannourakis, Prithviraj and Ahmed.
Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma
- Sharma, Revati, Kadife, Elif, Myers, Mark, Kannourakis, George, Prithviraj, Prashanth, Ahmed, Nuzhat
- Authors: Sharma, Revati , Kadife, Elif , Myers, Mark , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2021
- Type: Text , Journal article , Review
- Relation: Journal of Experimental and Clinical Cancer Research Vol. 40, no. 1 (2021), p.
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- Description: Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies. © 2021, The Author(s).
- Authors: Sharma, Revati , Kadife, Elif , Myers, Mark , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2021
- Type: Text , Journal article , Review
- Relation: Journal of Experimental and Clinical Cancer Research Vol. 40, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies. © 2021, The Author(s).
The attributes of plakins in cancer and disease: perspectives on ovarian cancer progression, chemoresistance and recurrence
- Wesley, Tamsin, Berzins, Stuart, Kannourakis, George, Ahmed, Nuzhat
- Authors: Wesley, Tamsin , Berzins, Stuart , Kannourakis, George , Ahmed, Nuzhat
- Date: 2021
- Type: Text , Journal article , Review
- Relation: Cell Communication and Signaling Vol. 19, no. 1 (2021), p.
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- Description: The plakin family of cytoskeletal proteins play an important role in cancer progression yet are under-studied in cancer, especially ovarian cancer. These large cytoskeletal proteins have primary roles in the maintenance of cytoskeletal integrity but are also associated with scaffolds of intermediate filaments and hemidesmosomal adhesion complexes mediating signalling pathways that regulate cellular growth, migration, invasion and differentiation as well as stress response. Abnormalities of plakins, and the closely related spectraplakins, result in diseases of the skin, striated muscle and nervous tissue. Their prevalence in epithelial cells suggests that plakins may play a role in epithelial ovarian cancer progression and recurrence. In this review article, we explore the roles of plakins, particularly plectin, periplakin and envoplakin in disease-states and cancers with emphasis on ovarian cancer. We discuss the potential role the plakin family of proteins play in regulating cancer cell growth, survival, migration, invasion and drug resistance. We highlight potential relationships between plakins, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) and discuss how interaction of these processes may affect ovarian cancer progression, chemoresistance and ultimately recurrence. We propose that molecular changes in the expression of plakins leads to the transition of benign ovarian tumours to carcinomas, as well as floating cellular aggregates (commonly known as spheroids) in the ascites microenvironment, which may contribute to the sustenance and progression of the disease. In this review, attempts have been made to understand the crucial changes in plakin expression in relation to progression and recurrence of ovarian cancer. [MediaObject not available: see fulltext.] © 2021, The Author(s).
- Authors: Wesley, Tamsin , Berzins, Stuart , Kannourakis, George , Ahmed, Nuzhat
- Date: 2021
- Type: Text , Journal article , Review
- Relation: Cell Communication and Signaling Vol. 19, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: The plakin family of cytoskeletal proteins play an important role in cancer progression yet are under-studied in cancer, especially ovarian cancer. These large cytoskeletal proteins have primary roles in the maintenance of cytoskeletal integrity but are also associated with scaffolds of intermediate filaments and hemidesmosomal adhesion complexes mediating signalling pathways that regulate cellular growth, migration, invasion and differentiation as well as stress response. Abnormalities of plakins, and the closely related spectraplakins, result in diseases of the skin, striated muscle and nervous tissue. Their prevalence in epithelial cells suggests that plakins may play a role in epithelial ovarian cancer progression and recurrence. In this review article, we explore the roles of plakins, particularly plectin, periplakin and envoplakin in disease-states and cancers with emphasis on ovarian cancer. We discuss the potential role the plakin family of proteins play in regulating cancer cell growth, survival, migration, invasion and drug resistance. We highlight potential relationships between plakins, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) and discuss how interaction of these processes may affect ovarian cancer progression, chemoresistance and ultimately recurrence. We propose that molecular changes in the expression of plakins leads to the transition of benign ovarian tumours to carcinomas, as well as floating cellular aggregates (commonly known as spheroids) in the ascites microenvironment, which may contribute to the sustenance and progression of the disease. In this review, attempts have been made to understand the crucial changes in plakin expression in relation to progression and recurrence of ovarian cancer. [MediaObject not available: see fulltext.] © 2021, The Author(s).
A role for MAIT cells in colorectal cancer
- Berzins, Stuart, Wallace, Morgan, Kannourakis, George, Kelly, Jason
- Authors: Berzins, Stuart , Wallace, Morgan , Kannourakis, George , Kelly, Jason
- Date: 2020
- Type: Text , Journal article , Review
- Relation: Frontiers in Immunology Vol. 11, no. (2020), p.
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- Description: MAIT cells are MR1-restricted T cells that are well-known for their anti-microbial properties, but they have recently been associated with different forms of cancer. Several studies have reported activated MAIT cells within the microenvironment of colorectal tumors, but there is conjecture about the nature of their response and whether they are contributing to anti-tumor immunity, or to the progression of the disease. We have reviewed the current state of knowledge about the role of MAIT cells in colorectal cancer, including their likely influence when activated and potential sources of stimulation in the tumor microenvironment. The prospects for MAIT cells being used in clinical settings as biomarkers or as targets of new immunotherapies designed to harness their function are discussed. © Copyright © 2020 Berzins, Wallace, Kannourakis and Kelly.
- Authors: Berzins, Stuart , Wallace, Morgan , Kannourakis, George , Kelly, Jason
- Date: 2020
- Type: Text , Journal article , Review
- Relation: Frontiers in Immunology Vol. 11, no. (2020), p.
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- Reviewed:
- Description: MAIT cells are MR1-restricted T cells that are well-known for their anti-microbial properties, but they have recently been associated with different forms of cancer. Several studies have reported activated MAIT cells within the microenvironment of colorectal tumors, but there is conjecture about the nature of their response and whether they are contributing to anti-tumor immunity, or to the progression of the disease. We have reviewed the current state of knowledge about the role of MAIT cells in colorectal cancer, including their likely influence when activated and potential sources of stimulation in the tumor microenvironment. The prospects for MAIT cells being used in clinical settings as biomarkers or as targets of new immunotherapies designed to harness their function are discussed. © Copyright © 2020 Berzins, Wallace, Kannourakis and Kelly.
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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- 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
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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.
A potentially important role for T cells and regulatory T cells in Langerhans cell histiocytosis
- Mitchell, Jenée, Berzins, Stuart, Kannourakis, George
- Authors: Mitchell, Jenée , Berzins, Stuart , Kannourakis, George
- Date: 2018
- Type: Text , Journal article , Review
- Relation: Clinical Immunology Vol. 194, no. (2018), p. 19-25
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- Reviewed:
- Description: Langerhans cell histiocytosis is characterized by lesions containing inflammatory immune cells, including myeloid cells and T cells. Patient mortality remains unacceptably high and new treatment options are required. Several LCH studies have identified aberrant frequencies of T cell subsets with potential immune regulatory properties. High numbers of Foxp3+ regulatory T cells and gamma-delta T cells have been reported in patients with LCH, although, the cause of their presence or their significance is not yet clear. This review describes the current understanding of how LCH develops and progresses, focusing on the growing evidence that regulatory T cell subsets may be important and discussing the exciting potential for harnessing these cells to treat LCH using immune based therapies.
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
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- 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
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- 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.
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