A three-stage developmental pathway for human V
- Perriman, Louis, Tavakolinia, Naeimeh, Jalali, Sedigheh, Li, Shuo, Hickey, Peter, Amann-Zalcenstein, Daniela, Ho, William, Baldwin, Tracey, Piers, Adam, Konstantinov, Igor, Anderson, Jeremy, Stanley, Edouard, Licciardi, Paul, Kannourakis, George, Naik, Shalin, Koay, Hui-Fern, Mackay, Laura, Berzins, Stuart, Pellicci, Daniel
- Authors: Perriman, Louis , Tavakolinia, Naeimeh , Jalali, Sedigheh , Li, Shuo , Hickey, Peter , Amann-Zalcenstein, Daniela , Ho, William , Baldwin, Tracey , Piers, Adam , Konstantinov, Igor , Anderson, Jeremy , Stanley, Edouard , Licciardi, Paul , Kannourakis, George , Naik, Shalin , Koay, Hui-Fern , Mackay, Laura , Berzins, Stuart , Pellicci, Daniel
- Date: 2023
- Type: Text , Journal article
- Relation: Science Immunology Vol. 8, no. 85 (2023), p.
- Full Text: false
- Reviewed:
- Description: V
Divergent molecular networks program functionally distinct CD8+skin-resident memory T cells
- Park, Simone, Christo, Susan, Wells, Alexandria, Gandolfo, Luke, Zaid, Ali, Alexandre, Yannick, Burn, Thomas, Schröder, Jan, Collins, Nicholas, Han, Seong-Ji, Guillaume, Stephane, Evrard, Maximilien, Castellucci, Clara, Davies, Brooke, Osman, Maleika, Obers, Andreas, McDonald, Keely, Wang, Huimeng, Mueller, Scott, Kannourakis, George, Berzins, Stuart, Mielke, Lisa, Carbone, Francis, Kallies, Axel, Speed, Terence, Belkaid, Yasmine, MacKay, Laura
- Authors: Park, Simone , Christo, Susan , Wells, Alexandria , Gandolfo, Luke , Zaid, Ali , Alexandre, Yannick , Burn, Thomas , Schröder, Jan , Collins, Nicholas , Han, Seong-Ji , Guillaume, Stephane , Evrard, Maximilien , Castellucci, Clara , Davies, Brooke , Osman, Maleika , Obers, Andreas , McDonald, Keely , Wang, Huimeng , Mueller, Scott , Kannourakis, George , Berzins, Stuart , Mielke, Lisa , Carbone, Francis , Kallies, Axel , Speed, Terence , Belkaid, Yasmine , MacKay, Laura
- Date: 2023
- Type: Text , Journal article
- Relation: Science Vol. 382, no. 6674 (2023), p. 1073-1079
- Full Text: false
- Reviewed:
- Description: Skin-resident CD8+T cells include distinct interferon-g-producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity. © 2023 American Association for the Advancement of Science. All rights reserved.
In vitro and in silico analysis of epithelial-mesenchymal transition and cancer stemness as prognostic markers of clear cell renal cell carcinoma
- Sharma, Revati, Balta, Showan, Raza, Ali, Escalona, Ruth, Kannourakis, George, Prithviraj, Prashanth, Ahmed, Nuzhat
- Authors: Sharma, Revati , Balta, Showan , Raza, Ali , Escalona, Ruth , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2023
- Type: Text , Journal article
- Relation: Cancers Vol. 15, no. 9 (2023), p.
- Full Text:
- Reviewed:
- Description: The process of epithelial-mesenchymal transition (EMT) involves the phenotypic transformation of cells from epithelial to mesenchymal status. The cells exhibiting EMT contain features of cancer stem cells (CSC), and the dual processes are responsible for progressive cancers. Activation of hypoxia-inducible factors (HIF) is fundamental to the pathogenesis of clear cell renal cell carcinoma (ccRCC), and their role in promoting EMT and CSCs is crucial for ccRCC tumour cell survival, disease progression, and metastatic spread. In this study, we explored the status of HIF genes and their downstream targets, EMT and CSC markers, by immunohistochemistry on in-house accrued ccRCC biopsies and adjacent non-tumorous tissues from patients undergoing partial or radical nephrectomy. In combination, we comprehensively analysed the expression of HIF genes and its downstream EMT and CSC-associated targets relevant to ccRCC by using publicly available datasets, the cancer genome atlas (TCGA) and the clinical proteome tumour analysis consortium (CPTAC). The aim was to search for novel biological prognostic markers that can stratify high-risk patients likely to experience metastatic disease. Using the above two approaches, we report the development of novel gene signatures that may help to identify patients at a high risk of developing metastatic and progressive disease. © 2023 by the authors.
- Authors: Sharma, Revati , Balta, Showan , Raza, Ali , Escalona, Ruth , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
- Date: 2023
- Type: Text , Journal article
- Relation: Cancers Vol. 15, no. 9 (2023), p.
- Full Text:
- Reviewed:
- Description: The process of epithelial-mesenchymal transition (EMT) involves the phenotypic transformation of cells from epithelial to mesenchymal status. The cells exhibiting EMT contain features of cancer stem cells (CSC), and the dual processes are responsible for progressive cancers. Activation of hypoxia-inducible factors (HIF) is fundamental to the pathogenesis of clear cell renal cell carcinoma (ccRCC), and their role in promoting EMT and CSCs is crucial for ccRCC tumour cell survival, disease progression, and metastatic spread. In this study, we explored the status of HIF genes and their downstream targets, EMT and CSC markers, by immunohistochemistry on in-house accrued ccRCC biopsies and adjacent non-tumorous tissues from patients undergoing partial or radical nephrectomy. In combination, we comprehensively analysed the expression of HIF genes and its downstream EMT and CSC-associated targets relevant to ccRCC by using publicly available datasets, the cancer genome atlas (TCGA) and the clinical proteome tumour analysis consortium (CPTAC). The aim was to search for novel biological prognostic markers that can stratify high-risk patients likely to experience metastatic disease. Using the above two approaches, we report the development of novel gene signatures that may help to identify patients at a high risk of developing metastatic and progressive disease. © 2023 by the authors.
The Interleukin-11/IL-11 receptor promotes glioblastoma survival and invasion under glucose-starved conditions through enhanced glutaminolysis
- Stuart, Sarah, Bezawork-Geleta, Ayenachew, Areeb, Zammam, Gomez, Juliana, Tsui, Vanessa, Zulkifli, Ahmad, Paradiso, Lucia, Jones, Jordan, Nguyen, Hong, Putoczki, Tracy, Licciardi, Paul, Kannourakis, George, Morokoff, Andrew, Achuthan, Adrian, Luwor, Rodney
- Authors: Stuart, Sarah , Bezawork-Geleta, Ayenachew , Areeb, Zammam , Gomez, Juliana , Tsui, Vanessa , Zulkifli, Ahmad , Paradiso, Lucia , Jones, Jordan , Nguyen, Hong , Putoczki, Tracy , Licciardi, Paul , Kannourakis, George , Morokoff, Andrew , Achuthan, Adrian , Luwor, Rodney
- Date: 2023
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 24, no. 4 (2023), p.
- Full Text:
- Reviewed:
- Description: Glioblastoma cells adapt to changes in glucose availability through metabolic plasticity allowing for cell survival and continued progression in low-glucose concentrations. However, the regulatory cytokine networks that govern the ability to survive in glucose-starved conditions are not fully defined. In the present study, we define a critical role for the IL-11/IL-11R
- Authors: Stuart, Sarah , Bezawork-Geleta, Ayenachew , Areeb, Zammam , Gomez, Juliana , Tsui, Vanessa , Zulkifli, Ahmad , Paradiso, Lucia , Jones, Jordan , Nguyen, Hong , Putoczki, Tracy , Licciardi, Paul , Kannourakis, George , Morokoff, Andrew , Achuthan, Adrian , Luwor, Rodney
- Date: 2023
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 24, no. 4 (2023), p.
- Full Text:
- Reviewed:
- Description: Glioblastoma cells adapt to changes in glucose availability through metabolic plasticity allowing for cell survival and continued progression in low-glucose concentrations. However, the regulatory cytokine networks that govern the ability to survive in glucose-starved conditions are not fully defined. In the present study, we define a critical role for the IL-11/IL-11R
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
- 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.
- 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.
Expression of TIMPs and MMPs in ovarian tumors, ascites, ascites-derived cells, and cancer cell lines : characteristic modulatory response before and after chemotherapy treatment
- Escalona, Ruth, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Escalona, Ruth , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article
- Relation: Frontiers in Oncology Vol. 11, no. (2022), p.
- Full Text:
- Reviewed:
- Description: Background: The tissue inhibitors of metalloproteinase (TIMPs) and their associated metalloproteinase (MMPs) are essential regulators of tissue homeostasis and are essential for cancer progression. This study analyzed the expression of TIMP-1,-2,-3 and the associated MMPs (MMP-2,-9,-11,-14) in different Stages, Grades and World Health Organization (WHO) classifications of serous ovarian tumors, ascites, ascites-derived cells from chemo-naïve (CN) and relapsed (CR) patients, and in ovarian cancer cell lines. The status of TIMPs and associated MMPs in response to chemotherapy treatment was assessed in cancer cell lines; TCGA data was interrogated to gauge TIMPs and associated MMPs as prognostic and platinum-response indicators. Methods: The levels of TIMP-1, -2 and -3 were assessed by immunohistochemistry. The mRNA expression of TIMPs and MMPs was quantified by real time PCR (qRT-PCR). The chemosensitivity (IC50 values) to Cisplatin or Paclitaxel in cell lines was evaluated by MTT assay. The levels of TIMPs in ascites and cell lysates were analyzed by an ELISA assay. Results: The expression of TIMP-2 was significantly upregulated in Type 2 compared to Type 1 tumors and normal/benign ovarian tissues. TIMP-3 expression was significantly enhanced in Stage III, Grade 3 and Type 2 tumors compared to normal/benign ovarian tissues. The mRNA expression of MMP-9,-11 and -14 was significantly upregulated in Stage IV compared to normal/benign ovarian tissues. The expression of TIMP-1 was highest, followed by TIMP-2 and then TIMP-3 in CN ascites. At the cellular level, TIMP-2 mRNA expression was significantly higher in CN compared to CR epithelial cells in patients. The expression of TIMP-1 and -2, MMPs and cancer stem cells (CSCs) were upregulated in response to chemotherapy treatments in cancer cell lines. Interrogation of the TCGA dataset suggests shifts in platinum responses in patients consistent with genetic alterations in TIMP-2, -3 and MMP-2, -11 genes in tumors; and decreased overall survival (OS) and progression-free survival (PFS) in patients with altered MMP-14 genes. Conclusions: TIMPs and related MMPs are differentially expressed in serous ovarian tumors, ascites, ascites-derived cells and ovarian cancer cell lines. Chemotherapy treatment modulates expression of TIMPs and MMPs in association with increased expression of genes related to cancer stem cells. Copyright © 2022 Escalona, Kannourakis, Findlay and Ahmed.
- Authors: Escalona, Ruth , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article
- Relation: Frontiers in Oncology Vol. 11, no. (2022), p.
- Full Text:
- Reviewed:
- Description: Background: The tissue inhibitors of metalloproteinase (TIMPs) and their associated metalloproteinase (MMPs) are essential regulators of tissue homeostasis and are essential for cancer progression. This study analyzed the expression of TIMP-1,-2,-3 and the associated MMPs (MMP-2,-9,-11,-14) in different Stages, Grades and World Health Organization (WHO) classifications of serous ovarian tumors, ascites, ascites-derived cells from chemo-naïve (CN) and relapsed (CR) patients, and in ovarian cancer cell lines. The status of TIMPs and associated MMPs in response to chemotherapy treatment was assessed in cancer cell lines; TCGA data was interrogated to gauge TIMPs and associated MMPs as prognostic and platinum-response indicators. Methods: The levels of TIMP-1, -2 and -3 were assessed by immunohistochemistry. The mRNA expression of TIMPs and MMPs was quantified by real time PCR (qRT-PCR). The chemosensitivity (IC50 values) to Cisplatin or Paclitaxel in cell lines was evaluated by MTT assay. The levels of TIMPs in ascites and cell lysates were analyzed by an ELISA assay. Results: The expression of TIMP-2 was significantly upregulated in Type 2 compared to Type 1 tumors and normal/benign ovarian tissues. TIMP-3 expression was significantly enhanced in Stage III, Grade 3 and Type 2 tumors compared to normal/benign ovarian tissues. The mRNA expression of MMP-9,-11 and -14 was significantly upregulated in Stage IV compared to normal/benign ovarian tissues. The expression of TIMP-1 was highest, followed by TIMP-2 and then TIMP-3 in CN ascites. At the cellular level, TIMP-2 mRNA expression was significantly higher in CN compared to CR epithelial cells in patients. The expression of TIMP-1 and -2, MMPs and cancer stem cells (CSCs) were upregulated in response to chemotherapy treatments in cancer cell lines. Interrogation of the TCGA dataset suggests shifts in platinum responses in patients consistent with genetic alterations in TIMP-2, -3 and MMP-2, -11 genes in tumors; and decreased overall survival (OS) and progression-free survival (PFS) in patients with altered MMP-14 genes. Conclusions: TIMPs and related MMPs are differentially expressed in serous ovarian tumors, ascites, ascites-derived cells and ovarian cancer cell lines. Chemotherapy treatment modulates expression of TIMPs and MMPs in association with increased expression of genes related to cancer stem cells. Copyright © 2022 Escalona, Kannourakis, Findlay and Ahmed.
Knock down of TIMP-2 by siRNA and CRISPR/Cas9 mediates diverse cellular reprogramming of metastasis and chemosensitivity in ovarian cancer
- Escalona, Ruth, Chu, Simon, Kadife, Elif, Kelly, Jason, Kannourakis, George, Findlay, Jock, Ahmed, Nuzhat
- Authors: Escalona, Ruth , Chu, Simon , Kadife, Elif , Kelly, Jason , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article
- Relation: Cancer Cell International Vol. 22, no. 1 (2022), p.
- Full Text:
- Reviewed:
- Description: Background: The endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2), through its homeostatic action on certain metalloproteinases, plays a vital role in remodelling extracellular matrix (ECM) to facilitate cancer progression. This study investigated the role of TIMP-2 in an ovarian cancer cell line in which the expression of TIMP-2 was reduced by either siRNA or CRISPR/Cas9. Methods: OVCAR5 cells were transiently and stably transfected with either single or pooled TIMP-2 siRNAs (T2-KD cells) or by CRISPR/Cas9 under the influence of two distinct guide RNAs (gRNA1 and gRNA2 cell lines). The expression of different genes was analysed at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence (IF) and western blot. Proliferation of cells was investigated by 5-Ethynyl-2′-deoxyuridine (EdU) assay or staining with Ki67. Cell migration/invasion was determined by xCELLigence. Cell growth in vitro was determined by 3D spheroid cultures and in vivo by a mouse xenograft model. Results: Approximately 70–90% knock down of TIMP-2 expression were confirmed in T2-KD, gRNA1 and gRNA2 OVCAR5 ovarian cancer cells at the protein level. T2-KD, gRNA1 and gRNA2 cells exhibited a significant downregulation of MMP-2 expression, but concurrently a significant upregulation in the expression of membrane bound MMP-14 compared to control and parental cells. Enhanced proliferation and invasion were exhibited in all TIMP-2 knocked down cells but differences in sensitivity to paclitaxel (PTX) treatment were observed, with T2-KD cells and gRNA2 cell line being sensitive, while the gRNA1 cell line was resistant to PTX treatment. In addition, significant differences in the growth of gRNA1 and gRNA2 cell lines were observed in in vitro 3D cultures as well as in an in vivo mouse xenograft model. Conclusions: Our results suggest that the inhibition of TIMP-2 by siRNA and CRISPR/Cas-9 modulate the expression of MMP-2 and MMP-14 and reprogram ovarian cancer cells to facilitate proliferation and invasion. Distinct disparities in in vitro chemosensitivity and growth in 3D culture, and differences in tumour burden and invasion to proximal organs in a mouse model imply that selective suppression of TIMP-2 expression by siRNA or CRISPR/Cas-9 alters important aspects of metastasis and chemosensitivity in ovarian cancer. © 2022, The Author(s).
- Authors: Escalona, Ruth , Chu, Simon , Kadife, Elif , Kelly, Jason , Kannourakis, George , Findlay, Jock , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article
- Relation: Cancer Cell International Vol. 22, no. 1 (2022), p.
- Full Text:
- Reviewed:
- Description: Background: The endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2), through its homeostatic action on certain metalloproteinases, plays a vital role in remodelling extracellular matrix (ECM) to facilitate cancer progression. This study investigated the role of TIMP-2 in an ovarian cancer cell line in which the expression of TIMP-2 was reduced by either siRNA or CRISPR/Cas9. Methods: OVCAR5 cells were transiently and stably transfected with either single or pooled TIMP-2 siRNAs (T2-KD cells) or by CRISPR/Cas9 under the influence of two distinct guide RNAs (gRNA1 and gRNA2 cell lines). The expression of different genes was analysed at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence (IF) and western blot. Proliferation of cells was investigated by 5-Ethynyl-2′-deoxyuridine (EdU) assay or staining with Ki67. Cell migration/invasion was determined by xCELLigence. Cell growth in vitro was determined by 3D spheroid cultures and in vivo by a mouse xenograft model. Results: Approximately 70–90% knock down of TIMP-2 expression were confirmed in T2-KD, gRNA1 and gRNA2 OVCAR5 ovarian cancer cells at the protein level. T2-KD, gRNA1 and gRNA2 cells exhibited a significant downregulation of MMP-2 expression, but concurrently a significant upregulation in the expression of membrane bound MMP-14 compared to control and parental cells. Enhanced proliferation and invasion were exhibited in all TIMP-2 knocked down cells but differences in sensitivity to paclitaxel (PTX) treatment were observed, with T2-KD cells and gRNA2 cell line being sensitive, while the gRNA1 cell line was resistant to PTX treatment. In addition, significant differences in the growth of gRNA1 and gRNA2 cell lines were observed in in vitro 3D cultures as well as in an in vivo mouse xenograft model. Conclusions: Our results suggest that the inhibition of TIMP-2 by siRNA and CRISPR/Cas-9 modulate the expression of MMP-2 and MMP-14 and reprogram ovarian cancer cells to facilitate proliferation and invasion. Distinct disparities in in vitro chemosensitivity and growth in 3D culture, and differences in tumour burden and invasion to proximal organs in a mouse model imply that selective suppression of TIMP-2 expression by siRNA or CRISPR/Cas-9 alters important aspects of metastasis and chemosensitivity in ovarian cancer. © 2022, The Author(s).
Plasma signaling factors in patients with langerhans cell histiocytosis (LCH) correlate with relative frequencies of LCH cells and t cells within lesions
- Mitchell, Jenée, Kvedaraite, Egle, von Bahr Greenwood, Tatiana, Lourda, Magda, Henter, Jan-Inge, Berzins, Stuart, Kannourakis, George
- Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Lourda, Magda , Henter, Jan-Inge , Berzins, Stuart , Kannourakis, George
- Date: 2022
- Type: Text , Journal article
- Relation: Frontiers in Pediatrics Vol. 10, no. (2022), p.
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) lesions contain an inflammatory infiltrate of immune cells including myeloid-derived LCH cells. Cell-signaling proteins within the lesion environment suggest that LCH cells and T cells contribute majorly to the inflammation. Foxp3+ regulatory T cells (Tregs) are enriched in lesions and blood from patients with LCH and are likely involved in LCH pathogenesis. In contrast, mucosal associated invariant T (MAIT) cells are reduced in blood from these patients and the consequence of this is unknown. Serum/plasma levels of cytokines have been associated with LCH disease extent and may play a role in the recruitment of cells to lesions. We investigated whether plasma signaling factors differed between patients with active and non-active LCH. Cell-signaling factors (38 analytes total) were measured in patient plasma and cell populations from matched lesions and/or peripheral blood were enumerated. This study aimed at understanding whether plasma factors corresponded with LCH cells and/or LCH-associated T cell subsets in patients with LCH. We identified several associations between plasma factors and lesional/circulating immune cell populations, thus highlighting new factors as potentially important in LCH pathogenesis. This study highlights plasma cell-signaling factors that are associated with LCH cells, MAIT cells or Tregs in patients, thus they are potentially important in LCH pathogenesis. Further study into these associations is needed to determine whether these factors may become suitable prognostic indicators or therapeutic targets to benefit patients. Copyright © 2022 Mitchell, Kvedaraite, von Bahr Greenwood, Lourda, Henter, Berzins and Kannourakis.
- Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Lourda, Magda , Henter, Jan-Inge , Berzins, Stuart , Kannourakis, George
- Date: 2022
- Type: Text , Journal article
- Relation: Frontiers in Pediatrics Vol. 10, no. (2022), p.
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) lesions contain an inflammatory infiltrate of immune cells including myeloid-derived LCH cells. Cell-signaling proteins within the lesion environment suggest that LCH cells and T cells contribute majorly to the inflammation. Foxp3+ regulatory T cells (Tregs) are enriched in lesions and blood from patients with LCH and are likely involved in LCH pathogenesis. In contrast, mucosal associated invariant T (MAIT) cells are reduced in blood from these patients and the consequence of this is unknown. Serum/plasma levels of cytokines have been associated with LCH disease extent and may play a role in the recruitment of cells to lesions. We investigated whether plasma signaling factors differed between patients with active and non-active LCH. Cell-signaling factors (38 analytes total) were measured in patient plasma and cell populations from matched lesions and/or peripheral blood were enumerated. This study aimed at understanding whether plasma factors corresponded with LCH cells and/or LCH-associated T cell subsets in patients with LCH. We identified several associations between plasma factors and lesional/circulating immune cell populations, thus highlighting new factors as potentially important in LCH pathogenesis. This study highlights plasma cell-signaling factors that are associated with LCH cells, MAIT cells or Tregs in patients, thus they are potentially important in LCH pathogenesis. Further study into these associations is needed to determine whether these factors may become suitable prognostic indicators or therapeutic targets to benefit patients. Copyright © 2022 Mitchell, Kvedaraite, von Bahr Greenwood, Lourda, Henter, Berzins and Kannourakis.
Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism
- Leung, Dilys, Price, Zoe, Lokman, Noor, Wang, Wanqi, Goonetilleke, Lizamarie, Kadife, Elif, Oehler, Martin, Ricciardelli, Carmela, Kannourakis, George, Ahmed, Nuzhat
- Authors: Leung, Dilys , Price, Zoe , Lokman, Noor , Wang, Wanqi , Goonetilleke, Lizamarie , Kadife, Elif , Oehler, Martin , Ricciardelli, Carmela , Kannourakis, George , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article
- Relation: Journal of Translational Medicine Vol. 20, no. 1 (2022), p.
- Full Text:
- Reviewed:
- Description: Background: Epithelial ovarian cancer is the most lethal gynaecological cancer worldwide. Chemotherapy resistance represents a significant clinical challenge and is the main reason for poor ovarian cancer prognosis. We identified novel expression of markers related to epithelial mesenchymal transitions (EMT) in a carboplatin resistant ovarian cancer cell line by proteomics. This was validated in the platinum resistant versus sensitive parental cell lines, as well as platinum resistant versus sensitive human ovarian cancer patient samples. The prognostic significance of the different proteomics-identified marker proteins in prognosis prediction on survival as well as their correlative association and influence on immune cell infiltration was determined by public domain data bases. Methods: We explored the proteomic differences between carboplatin-sensitive OVCAR5 cells (parental) and their carboplatin-resistant counterpart, OVCAR5 CBPR cells. qPCR and western blots were performed to validate differentially expressed proteins at the mRNA and protein levels, respectively. Association of the identified proteins with epithelial–mesenchymal transition (EMT) prompted the investigation of cell motility. Cellular bioenergetics and proliferation were studied to delineate any biological adaptations that facilitate cancer progression. Expression of differentially expressed proteins was assessed in ovarian tumors obtained from platinum-sensitive (n = 15) versus platinum-resistant patients (n = 10), as well as matching tumors from patients at initial diagnosis and following relapse (n = 4). Kaplan–Meier plotter and Tumor Immune Estimation Resource (TIMER) databases were used to determine the prognostic significance and influence of the different proteomics-identified proteins on immune cell infiltration in the tumor microenvironment (TME). Results: Our proteomics study identified 2422 proteins in both cell lines. Of these, 18 proteins were upregulated and 14 were downregulated by
- Authors: Leung, Dilys , Price, Zoe , Lokman, Noor , Wang, Wanqi , Goonetilleke, Lizamarie , Kadife, Elif , Oehler, Martin , Ricciardelli, Carmela , Kannourakis, George , Ahmed, Nuzhat
- Date: 2022
- Type: Text , Journal article
- Relation: Journal of Translational Medicine Vol. 20, no. 1 (2022), p.
- Full Text:
- Reviewed:
- Description: Background: Epithelial ovarian cancer is the most lethal gynaecological cancer worldwide. Chemotherapy resistance represents a significant clinical challenge and is the main reason for poor ovarian cancer prognosis. We identified novel expression of markers related to epithelial mesenchymal transitions (EMT) in a carboplatin resistant ovarian cancer cell line by proteomics. This was validated in the platinum resistant versus sensitive parental cell lines, as well as platinum resistant versus sensitive human ovarian cancer patient samples. The prognostic significance of the different proteomics-identified marker proteins in prognosis prediction on survival as well as their correlative association and influence on immune cell infiltration was determined by public domain data bases. Methods: We explored the proteomic differences between carboplatin-sensitive OVCAR5 cells (parental) and their carboplatin-resistant counterpart, OVCAR5 CBPR cells. qPCR and western blots were performed to validate differentially expressed proteins at the mRNA and protein levels, respectively. Association of the identified proteins with epithelial–mesenchymal transition (EMT) prompted the investigation of cell motility. Cellular bioenergetics and proliferation were studied to delineate any biological adaptations that facilitate cancer progression. Expression of differentially expressed proteins was assessed in ovarian tumors obtained from platinum-sensitive (n = 15) versus platinum-resistant patients (n = 10), as well as matching tumors from patients at initial diagnosis and following relapse (n = 4). Kaplan–Meier plotter and Tumor Immune Estimation Resource (TIMER) databases were used to determine the prognostic significance and influence of the different proteomics-identified proteins on immune cell infiltration in the tumor microenvironment (TME). Results: Our proteomics study identified 2422 proteins in both cell lines. Of these, 18 proteins were upregulated and 14 were downregulated by
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.
- Full Text:
- Reviewed:
- 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.
- Full Text:
- Reviewed:
- 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.
- 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).
- 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).
Does CD1a expression influence T cell function in patients with langerhans cell histiocytosis?
- Mitchell, Jenee, Kannourakis, George
- Authors: Mitchell, Jenee , Kannourakis, George
- Date: 2021
- Type: Text , Journal article
- Relation: Frontiers in Immunology Vol. 12, no. (2021), p.
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis lesions are characterized by CD1a+ myeloid lineage LCH cells and an inflammatory infiltrate of cytokines and immune cells, including T cells. T cells that recognize CD1a may be implicated in the pathology of many disease states including cancer and autoimmunity but have not been studied in the context of LCH despite the expression of CD1a by LCH cells. In this perspective article, we discuss the expression of CD1a by LCH cells, and we explore the potential for T cells that recognize CD1a to be involved in LCH pathogenesis. Copyright © 2021 Mitchell and Kannourakis.
- Authors: Mitchell, Jenee , Kannourakis, George
- Date: 2021
- Type: Text , Journal article
- Relation: Frontiers in Immunology Vol. 12, no. (2021), p.
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis lesions are characterized by CD1a+ myeloid lineage LCH cells and an inflammatory infiltrate of cytokines and immune cells, including T cells. T cells that recognize CD1a may be implicated in the pathology of many disease states including cancer and autoimmunity but have not been studied in the context of LCH despite the expression of CD1a by LCH cells. In this perspective article, we discuss the expression of CD1a by LCH cells, and we explore the potential for T cells that recognize CD1a to be involved in LCH pathogenesis. Copyright © 2021 Mitchell and Kannourakis.
Langerhans cell histiocytosis : a malignant myeloid neoplasm or disorder of immune regulation?
- Mitchell, Jenee, Kannourakis, George
- Authors: Mitchell, Jenee , Kannourakis, George
- Date: 2021
- Type: Text , Journal article
- Relation: Acta Paediatrica, International Journal of Paediatrics Vol. 110, no. 11 (2021), p. 2888-2891
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) is characterised by lesions containing LCH cells, which are myeloid-derived dendritic cells that co-express CD1a and CD207 (langerin). In addition to LCH cells, these lesions also contain an inflammatory microenvironment of T cells, macrophages, neutrophils, eosinophils, B cells, plasma cells and multinucleated giant cells. Whilst LCH cells are well studied (Figure 1) and important in the pathogenesis of this disease, the inflammatory infiltrate and the corresponding cytokine milieu they produce are central to the resultant organ damage, which is a hallmark of this disease.1 Although LCH is more common in young children, it occurs at all ages, and the resulting mortality/morbidity varies from lethal to mild despite similar pathology of biopsied lesions.
- Authors: Mitchell, Jenee , Kannourakis, George
- Date: 2021
- Type: Text , Journal article
- Relation: Acta Paediatrica, International Journal of Paediatrics Vol. 110, no. 11 (2021), p. 2888-2891
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) is characterised by lesions containing LCH cells, which are myeloid-derived dendritic cells that co-express CD1a and CD207 (langerin). In addition to LCH cells, these lesions also contain an inflammatory microenvironment of T cells, macrophages, neutrophils, eosinophils, B cells, plasma cells and multinucleated giant cells. Whilst LCH cells are well studied (Figure 1) and important in the pathogenesis of this disease, the inflammatory infiltrate and the corresponding cytokine milieu they produce are central to the resultant organ damage, which is a hallmark of this disease.1 Although LCH is more common in young children, it occurs at all ages, and the resulting mortality/morbidity varies from lethal to mild despite similar pathology of biopsied lesions.
Prognostic role of immune checkpoint regulators in cholangiocarcinoma : a pilot study
- Cao, Lu, Prithviraj, Prashanth, Shrestha, Ritu, Sharma, Revati, Kannourakis, George
- Authors: Cao, Lu , Prithviraj, Prashanth , Shrestha, Ritu , Sharma, Revati , Kannourakis, George
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Clinical Medicine Vol. 10, no. 10 (2021), p.
- Full Text:
- Reviewed:
- Description: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy associated with steadily increasing incidence and poor prognosis. Ongoing clinical trials are assessing the effectiveness and safety of a few immune checkpoint inhibitors (ICIs) in CCA patients. However, these ICI treatments as monotherapies may be effective for a proportion of patients with CCA. The prevalence and distribution of other immune checkpoints (ICs) in CCA remain unclear. In this pilot study, we screened databases of CCA patients for the expression of 19 ICs and assessed the prognostic significance of these ICs in CCA patients. Notably, expression of immune modulator IDO1 and PD-L1 were linked with poor overall survival, while FASLG and NT5E were related to both worse overall survival and progression-free survival. We also identified immune modulators IDO1, FASLG, CD80, HAVCR2, NT5E, CTLA-4, LGALS9, VTCN1 and TNFRSF14 that synergized with PD-L1 and correlated with worse patient outcomes. In vitro studies revealed that the expression of ICs was closely linked with aggressive CCA subpopulations, such as cancer stem cells and cells undergoing TGF-β and TNF-α-mediated epithelial-to-mesenchymal transition. These findings suggest that the aforementioned IC molecules may serve as potential prognostic biomarkers and drug targets in CCA patients, leading to lasting and durable treatment outcomes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Prashanth Prithviraj, Revati Sharma, George Kannourakis” is provided in this record**
- Authors: Cao, Lu , Prithviraj, Prashanth , Shrestha, Ritu , Sharma, Revati , Kannourakis, George
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Clinical Medicine Vol. 10, no. 10 (2021), p.
- Full Text:
- Reviewed:
- Description: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy associated with steadily increasing incidence and poor prognosis. Ongoing clinical trials are assessing the effectiveness and safety of a few immune checkpoint inhibitors (ICIs) in CCA patients. However, these ICI treatments as monotherapies may be effective for a proportion of patients with CCA. The prevalence and distribution of other immune checkpoints (ICs) in CCA remain unclear. In this pilot study, we screened databases of CCA patients for the expression of 19 ICs and assessed the prognostic significance of these ICs in CCA patients. Notably, expression of immune modulator IDO1 and PD-L1 were linked with poor overall survival, while FASLG and NT5E were related to both worse overall survival and progression-free survival. We also identified immune modulators IDO1, FASLG, CD80, HAVCR2, NT5E, CTLA-4, LGALS9, VTCN1 and TNFRSF14 that synergized with PD-L1 and correlated with worse patient outcomes. In vitro studies revealed that the expression of ICs was closely linked with aggressive CCA subpopulations, such as cancer stem cells and cells undergoing TGF-β and TNF-α-mediated epithelial-to-mesenchymal transition. These findings suggest that the aforementioned IC molecules may serve as potential prognostic biomarkers and drug targets in CCA patients, leading to lasting and durable treatment outcomes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Prashanth Prithviraj, Revati Sharma, George Kannourakis” is provided in this record**
Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes
- Evrard, Maximilien, Wynne-Jones, Erica, Peng, Changwei, Kannourakis, George, Berzins, Stuart
- Authors: Evrard, Maximilien , Wynne-Jones, Erica , Peng, Changwei , Kannourakis, George , Berzins, Stuart
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Experimental Medicine Vol. 219, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes. © 2021 Evrard et al.
- Authors: Evrard, Maximilien , Wynne-Jones, Erica , Peng, Changwei , Kannourakis, George , Berzins, Stuart
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Experimental Medicine Vol. 219, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes. © 2021 Evrard et al.
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.
- 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).
- 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.
- Full Text:
- 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.
- 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.
- Full Text:
- 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.
Aberrant pregnancy-associated plasma protein-A expression in breast cancers prognosticates clinical outcomes
- Prithviraj, Prashanth, Anaka, Matthew, Thompson, Erik, Sharma, Revati, Walkiewicz, Marzena, Tutuka, Candani, Behren, Andreas, Kannourakis, George, Jayachandran, Aparna
- Authors: Prithviraj, Prashanth , Anaka, Matthew , Thompson, Erik , Sharma, Revati , Walkiewicz, Marzena , Tutuka, Candani , Behren, Andreas , Kannourakis, George , Jayachandran, Aparna
- Date: 2020
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 10, no. 1 (2020), p.
- Full Text:
- Reviewed:
- Description: Elevated levels of pregnancy-associated plasma protein-A (PAPP-A) have been implicated in the pathogenesis of various malignancies, including breast cancers. Breast cancer is one of the most frequent carcinomas and is the second most common cancer type detected in women of child-bearing age. Throughout pregnancy PAPP-A is produced and secreted by the placental syncytiotrophoblast cells; co-incidentally pregnancy-associated breast cancers often have an aggressive clinical course. The components of the PAPP-A/IGF axis was assessed in a panel of breast cancer cell lines. Using neutralising antibodies the impact of PAPP-A/IGF axis on cell motility was evaluated. PAPP-A was expressed in four of the twelve breast cancer cell lines tested. Blocking PAPP-A and IGFBP4 with neutralising antibodies significantly decreased motiliy of MDA-MB-231 cells. Upregulation of PAPP-A expression in breast tumours resulted in a trend towards worse overall survival. Notably, PAPP-A expression also positively correlated with epithelial-to-mesenchymal transition markers. In conclusion, these results indicate that PAPP-A plays an important role in breast cancer progression and it may be a promising therapeutic target in breast cancer. © 2020, The Author(s).
- Authors: Prithviraj, Prashanth , Anaka, Matthew , Thompson, Erik , Sharma, Revati , Walkiewicz, Marzena , Tutuka, Candani , Behren, Andreas , Kannourakis, George , Jayachandran, Aparna
- Date: 2020
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 10, no. 1 (2020), p.
- Full Text:
- Reviewed:
- Description: Elevated levels of pregnancy-associated plasma protein-A (PAPP-A) have been implicated in the pathogenesis of various malignancies, including breast cancers. Breast cancer is one of the most frequent carcinomas and is the second most common cancer type detected in women of child-bearing age. Throughout pregnancy PAPP-A is produced and secreted by the placental syncytiotrophoblast cells; co-incidentally pregnancy-associated breast cancers often have an aggressive clinical course. The components of the PAPP-A/IGF axis was assessed in a panel of breast cancer cell lines. Using neutralising antibodies the impact of PAPP-A/IGF axis on cell motility was evaluated. PAPP-A was expressed in four of the twelve breast cancer cell lines tested. Blocking PAPP-A and IGFBP4 with neutralising antibodies significantly decreased motiliy of MDA-MB-231 cells. Upregulation of PAPP-A expression in breast tumours resulted in a trend towards worse overall survival. Notably, PAPP-A expression also positively correlated with epithelial-to-mesenchymal transition markers. In conclusion, these results indicate that PAPP-A plays an important role in breast cancer progression and it may be a promising therapeutic target in breast cancer. © 2020, The Author(s).
- Mitchell, Jenée, Kelly, Jason, Kvedaraite, E., von Bahr Greenwood, Tatiana, Henter, Jan-Inge, Pellicci, Daniel, Berzins, Stuart, Kannourakis, George
- Authors: Mitchell, Jenée , Kelly, Jason , Kvedaraite, E. , von Bahr Greenwood, Tatiana , Henter, Jan-Inge , Pellicci, Daniel , Berzins, Stuart , Kannourakis, George
- Date: 2020
- Type: Text , Journal article
- Relation: Clinical Immunology Vol. 215, no. (2020), p.
- Full Text: false
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) lesions contain myeloid lineage ‘LCH’ cells. Regulatory T cells (Tregs) are also enriched within lesions, although their role in LCH pathogenesis is unknown. LCH cells are thought to produce the transforming growth factor beta (TGF-β) within lesions, however whether Tregs contribute is unestablished. Using flow cytometry, we analyzed relative frequencies of live Tregs from LCH patients and identified CD56 expression and TGF-β production by lesion Tregs. While CD56+ Tregs were enriched in lesions, overall CD56+ T cells were reduced in the blood from active LCH patients compared to non-active disease patients, and there was a negative correlation between CD8+CD56+ T cells and Tregs. We propose that inducing a Treg phenotype in T cells such as CD56+ T cells may be a mechanism by which LCH cells divert inflammatory T cell responses. Thus, Tregs within LCH lesions are likely an important component in LCH pathogenesis. © 2020
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
- 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.
- 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.