Pub Date : 2015-11-16DOI: 10.18632/ONCOSCIENCE.264
J. Cedervall, A. Olsson
A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. Although the awareness of tumor-induced systemic effects has increased significantly in recent years, current knowledge is still mainly restricted to metastatic sites. Surprisingly little is known about the situation in organs that are not targets for metastasis or directly affected by the primary tumor. We therefore decided to look deeper into this relatively unexplored field of cancer research. For obvious reasons human biopsy material from tissues not affected by tumor cells, in an individual with cancer, are rare and mouse models therefore become important tools for such investigations. Using two different orthotopic and spontaneously metastasizing tumor models - the RIP1-Tag2 model for insulinoma with metastasis to the liver and the MMTV-PyMT model for mammary carcinoma with lung metastasis - we analyzed the presence of hematopoietic cells in organs which do not represent sites for primary tumor growth. There was a significant increase in the number of neutrophils in heart and kidneys of tumor-bearing mice compared to healthy individuals [1]. In mice with cancer, peripheral organs displayed systemic inflammation and impaired vascular function, which was restored upon neutrophil depletion. Platelet/neutrophil complexes, indicative of neutrophil extracellular traps (NETs), were found in kidney and heart from tumor-bearing mice, while these complexes were completely absent in the corresponding tissues from healthy mice. Indeed, analysis of peripheral blood confirmed the presence of neutrophils with extracellular DNA-tails in tumor-bearing mice.
{"title":"NETosis in cancer","authors":"J. Cedervall, A. Olsson","doi":"10.18632/ONCOSCIENCE.264","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.264","url":null,"abstract":"A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. Although the awareness of tumor-induced systemic effects has increased significantly in recent years, current knowledge is still mainly restricted to metastatic sites. Surprisingly little is known about the situation in organs that are not targets for metastasis or directly affected by the primary tumor. We therefore decided to look deeper into this relatively unexplored field of cancer research. For obvious reasons human biopsy material from tissues not affected by tumor cells, in an individual with cancer, are rare and mouse models therefore become important tools for such investigations. Using two different orthotopic and spontaneously metastasizing tumor models - the RIP1-Tag2 model for insulinoma with metastasis to the liver and the MMTV-PyMT model for mammary carcinoma with lung metastasis - we analyzed the presence of hematopoietic cells in organs which do not represent sites for primary tumor growth. There was a significant increase in the number of neutrophils in heart and kidneys of tumor-bearing mice compared to healthy individuals [1]. In mice with cancer, peripheral organs displayed systemic inflammation and impaired vascular function, which was restored upon neutrophil depletion. Platelet/neutrophil complexes, indicative of neutrophil extracellular traps (NETs), were found in kidney and heart from tumor-bearing mice, while these complexes were completely absent in the corresponding tissues from healthy mice. Indeed, analysis of peripheral blood confirmed the presence of neutrophils with extracellular DNA-tails in tumor-bearing mice.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"4 1","pages":"900 - 901"},"PeriodicalIF":0.0,"publicationDate":"2015-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90189648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-15DOI: 10.18632/ONCOSCIENCE.263
Kideok Jin, S. Sukumar
HOXB7 is a homeodomain containing transcription factor which plays a pivotal role in tamoxifen resistant breast cancer. Our work has shown that overexpression of HOXB7 renders cells tamoxifen resistant by mobilizing a number of receptor tyrosine kinase pathways. EGFR expression is upregulated by direct binding of HOXB7 to the EGFR promoter, while HOXB7 functions as a cofactor with ERα to cause overexpression of multiple ER-target genes, including HER2, in tamoxifen resistant breast cancer cells. Probing the pathway further, we found that miR-196a and MYC are upstream regulators of HOXB7 expression. Mechanistically, HOXB7 and ERα jointly upregulate HER2 which phosphorylates MYC. Thus stabilized, MYC in turn suppresses miR-196a. Loss of miR-196a results lifts the quelling influence of miR-196a on HOXB7 expression. Besides shedding light on the intricate interplay of events occurring in tamoxifen resistant breast cancer, the work identifies a number of new therapeutic targets capable of restoring sensitivity of breast cancer cells to tamoxifen.
{"title":"A pivotal role for HOXB7 protein in endocrine resistant breast cancer","authors":"Kideok Jin, S. Sukumar","doi":"10.18632/ONCOSCIENCE.263","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.263","url":null,"abstract":"HOXB7 is a homeodomain containing transcription factor which plays a pivotal role in tamoxifen resistant breast cancer. Our work has shown that overexpression of HOXB7 renders cells tamoxifen resistant by mobilizing a number of receptor tyrosine kinase pathways. EGFR expression is upregulated by direct binding of HOXB7 to the EGFR promoter, while HOXB7 functions as a cofactor with ERα to cause overexpression of multiple ER-target genes, including HER2, in tamoxifen resistant breast cancer cells. Probing the pathway further, we found that miR-196a and MYC are upstream regulators of HOXB7 expression. Mechanistically, HOXB7 and ERα jointly upregulate HER2 which phosphorylates MYC. Thus stabilized, MYC in turn suppresses miR-196a. Loss of miR-196a results lifts the quelling influence of miR-196a on HOXB7 expression. Besides shedding light on the intricate interplay of events occurring in tamoxifen resistant breast cancer, the work identifies a number of new therapeutic targets capable of restoring sensitivity of breast cancer cells to tamoxifen.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"917 - 919"},"PeriodicalIF":0.0,"publicationDate":"2015-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89546764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-11DOI: 10.18632/ONCOSCIENCE.260
C. Panuzzo, G. Volpe, E. C. Rocchietti, C. Casnici, K. Crotta, S. Crivellaro, Giovanna Carrá, Roberta Lorenzatti, Barbara Peracino, Davide Torti, A. Morotti, M. P. Camacho-Leal, P. Defilippi, O. Marelli, G. Saglio
In Chronic Myeloid Leukemia 80% of patients present alternative splice variants involving BCR exons 1, 13 or 14 and ABL exon 4, with a consequent impairment in the reading frame of the ABL gene. Therefore BCR/ABL fusion proteins (BCR/ABL-OOF) are characterized by an in-frame BCR portion followed by an amino acids sequence arising from the out of frame (OOF) reading of the ABL gene. The product of this new transcript contains the characteristic BCR domains while lacking the COOH-terminal Rho GTPase GAP domain. The present work aims to characterize the protein functionality in terms of cytoskeleton (re-)modelling, adhesion and activation of canonical oncogenic signalling pathways. Here, we show that BCR/ABL-OOF has a peculiar endosomal localization which affects EGF receptor activation and turnover. Moreover, we demonstrate that BCR/ABL-OOF expression leads to aberrant cellular adhesion due to the activation of Rac GTPase, increase in cellular proliferation, migration and survival. When overexpressed in a BCR/ABL positive cell line, BCR/ABL-OOF induces hyperactivation of Rac signaling axis offering a therapeutic window for Rac-targeted therapy. Our data support a critical role of BCR/ABL-OOF in leukemogenesis and identify a subset of patients that may benefit from Rac-targeted therapies.
{"title":"New alternative splicing BCR/ABL-OOF shows an oncogenic role by lack of inhibition of BCR GTPase activity and an increased of persistence of Rac activation in chronic myeloid leukemia","authors":"C. Panuzzo, G. Volpe, E. C. Rocchietti, C. Casnici, K. Crotta, S. Crivellaro, Giovanna Carrá, Roberta Lorenzatti, Barbara Peracino, Davide Torti, A. Morotti, M. P. Camacho-Leal, P. Defilippi, O. Marelli, G. Saglio","doi":"10.18632/ONCOSCIENCE.260","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.260","url":null,"abstract":"In Chronic Myeloid Leukemia 80% of patients present alternative splice variants involving BCR exons 1, 13 or 14 and ABL exon 4, with a consequent impairment in the reading frame of the ABL gene. Therefore BCR/ABL fusion proteins (BCR/ABL-OOF) are characterized by an in-frame BCR portion followed by an amino acids sequence arising from the out of frame (OOF) reading of the ABL gene. The product of this new transcript contains the characteristic BCR domains while lacking the COOH-terminal Rho GTPase GAP domain. The present work aims to characterize the protein functionality in terms of cytoskeleton (re-)modelling, adhesion and activation of canonical oncogenic signalling pathways. Here, we show that BCR/ABL-OOF has a peculiar endosomal localization which affects EGF receptor activation and turnover. Moreover, we demonstrate that BCR/ABL-OOF expression leads to aberrant cellular adhesion due to the activation of Rac GTPase, increase in cellular proliferation, migration and survival. When overexpressed in a BCR/ABL positive cell line, BCR/ABL-OOF induces hyperactivation of Rac signaling axis offering a therapeutic window for Rac-targeted therapy. Our data support a critical role of BCR/ABL-OOF in leukemogenesis and identify a subset of patients that may benefit from Rac-targeted therapies.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"124 1","pages":"880 - 891"},"PeriodicalIF":0.0,"publicationDate":"2015-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76223000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-11DOI: 10.18632/ONCOSCIENCE.261
W. Arancio, S. Genovese, L. Bongiovanni, C. Tripodo
In genomic deletions, gene haploinsufficiency might directly configure a specific disease phenotype. Nevertheless, in some cases no functional association can be identified between haploinsufficient genes and the deletion-associated phenotype. Transcripts can act as microRNA sponges. The reduction of transcripts from the hemizygous region may increase the availability of specific microRNAs, which in turn may exert in-trans regulation of target genes outside the deleted region, eventually contributing to the phenotype. Here we prospect a competing endogenous RNA (ceRNA) approach for the identification of candidate genes target of epigenetic regulation in deletion syndromes. As a model, we analyzed the 5q- myelodysplastic syndrome. Genes in haploinsufficiency within the common 5q deleted region in CD34+ blasts were identified in silico. Using the miRWalk 2.0 platform, we predicted microRNAs whose availability, and thus activity, could be enhanced by the deletion, and performed a genomewide analysis of the genes outside the 5q deleted region that could be targeted by the predicted miRNAs. The analysis pointed to two genes with altered expression in 5q- transcriptome, which have never been related with 5q- before. The prospected approach allows investigating the global transcriptional effect of genomic deletions, possibly prompting discovery of unsuspected contributors in the deletion-associated phenotype. Moreover, it may help in functionally characterizing previously reported unexpected interactions.
{"title":"A ceRNA approach may unveil unexpected contributors to deletion syndromes, the model of 5q- syndrome","authors":"W. Arancio, S. Genovese, L. Bongiovanni, C. Tripodo","doi":"10.18632/ONCOSCIENCE.261","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.261","url":null,"abstract":"In genomic deletions, gene haploinsufficiency might directly configure a specific disease phenotype. Nevertheless, in some cases no functional association can be identified between haploinsufficient genes and the deletion-associated phenotype. Transcripts can act as microRNA sponges. The reduction of transcripts from the hemizygous region may increase the availability of specific microRNAs, which in turn may exert in-trans regulation of target genes outside the deleted region, eventually contributing to the phenotype. Here we prospect a competing endogenous RNA (ceRNA) approach for the identification of candidate genes target of epigenetic regulation in deletion syndromes. As a model, we analyzed the 5q- myelodysplastic syndrome. Genes in haploinsufficiency within the common 5q deleted region in CD34+ blasts were identified in silico. Using the miRWalk 2.0 platform, we predicted microRNAs whose availability, and thus activity, could be enhanced by the deletion, and performed a genomewide analysis of the genes outside the 5q deleted region that could be targeted by the predicted miRNAs. The analysis pointed to two genes with altered expression in 5q- transcriptome, which have never been related with 5q- before. The prospected approach allows investigating the global transcriptional effect of genomic deletions, possibly prompting discovery of unsuspected contributors in the deletion-associated phenotype. Moreover, it may help in functionally characterizing previously reported unexpected interactions.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"129 1","pages":"872 - 879"},"PeriodicalIF":0.0,"publicationDate":"2015-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76938055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-10DOI: 10.18632/ONCOSCIENCE.258
M. López-Lázaro
Metastasis will continue to be an incurable disease for most patients until we develop highly selective anticancer therapies. The development of these therapies requires finding and exploiting major differences between cancer cells and normal cells. Although the sum of the many DNA alterations of cancer cells makes up such a major difference, there is currently no way of exploiting these alterations as a whole. Here I propose a non-pharmacological strategy to selectively kill any type of cancer cell, including cancer stem cells, by exploiting their complete set of DNA alterations. It is based on creating challenging environmental conditions that only cells with undamaged DNAs can overcome. Cell survival requires continuous protein synthesis, which in turn requires adequate levels of 20 amino acids (AAs). If we temporarily restrict specific AAs and keep high levels of others whose deficit triggers proteolysis, we will force cells to activate a variety of genetic programs to obtain adequate levels of each of the 20 proteinogenic AAs. Because cancer cells have an extremely altered DNA that has evolved under particular environmental conditions, they may be unable to activate the genetic programs required to adapt to and survive the new environment. Cancer patients may be successfully treated with a protein-free artificial diet in which the levels of specific AAs are manipulated. Practical considerations for testing and implementing this cheap and universal anticancer strategy are discussed.
{"title":"Selective amino acid restriction therapy (SAART): a non-pharmacological strategy against all types of cancer cells","authors":"M. López-Lázaro","doi":"10.18632/ONCOSCIENCE.258","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.258","url":null,"abstract":"Metastasis will continue to be an incurable disease for most patients until we develop highly selective anticancer therapies. The development of these therapies requires finding and exploiting major differences between cancer cells and normal cells. Although the sum of the many DNA alterations of cancer cells makes up such a major difference, there is currently no way of exploiting these alterations as a whole. Here I propose a non-pharmacological strategy to selectively kill any type of cancer cell, including cancer stem cells, by exploiting their complete set of DNA alterations. It is based on creating challenging environmental conditions that only cells with undamaged DNAs can overcome. Cell survival requires continuous protein synthesis, which in turn requires adequate levels of 20 amino acids (AAs). If we temporarily restrict specific AAs and keep high levels of others whose deficit triggers proteolysis, we will force cells to activate a variety of genetic programs to obtain adequate levels of each of the 20 proteinogenic AAs. Because cancer cells have an extremely altered DNA that has evolved under particular environmental conditions, they may be unable to activate the genetic programs required to adapt to and survive the new environment. Cancer patients may be successfully treated with a protein-free artificial diet in which the levels of specific AAs are manipulated. Practical considerations for testing and implementing this cheap and universal anticancer strategy are discussed.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"33 1","pages":"857 - 866"},"PeriodicalIF":0.0,"publicationDate":"2015-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86821104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-10DOI: 10.18632/ONCOSCIENCE.259
J. Rennhack, E. Andrechek
To improve breast cancer patient outcome work must be done to understand and block tumor metastasis. This study leverages bioinformatics techniques and traditional genetic screens to create a novel method of discovering potential contributors of tumor progression with a focus on tumor metastasis. A database of 1172 of expression data from a variety of mouse models of breast cancer was assembled and queried using previously defined oncogenic activity signatures. This analysis revealed high activity of the E2F family of transcription factors in the MMTV-Neu mouse model. A genetic cross of MMTV-Neu mice into an E2F1 null, E2F2 null, or E2F3 heterozygous background revealed significant changes in tumor progression specifically reductions in tumor latency and metastasis with E2F1 or E2F2 loss. These findings were found to be conserved in human HER2 positive patients. Patients with high E2F1 activity were shown to have worse outcomes such as relapse free survival and distant metastasis free survival. This study shows conserved mechanisms of tumor progression in human breast cancer subtypes and analogous mouse models and underlies the importance of increased research into the characterization of and comparisons between mouse and human tumors to identify which mouse models resemble each subtype of human breast cancer.
{"title":"Conserved E2F mediated metastasis in mouse models of breast cancer and HER2 positive patients","authors":"J. Rennhack, E. Andrechek","doi":"10.18632/ONCOSCIENCE.259","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.259","url":null,"abstract":"To improve breast cancer patient outcome work must be done to understand and block tumor metastasis. This study leverages bioinformatics techniques and traditional genetic screens to create a novel method of discovering potential contributors of tumor progression with a focus on tumor metastasis. A database of 1172 of expression data from a variety of mouse models of breast cancer was assembled and queried using previously defined oncogenic activity signatures. This analysis revealed high activity of the E2F family of transcription factors in the MMTV-Neu mouse model. A genetic cross of MMTV-Neu mice into an E2F1 null, E2F2 null, or E2F3 heterozygous background revealed significant changes in tumor progression specifically reductions in tumor latency and metastasis with E2F1 or E2F2 loss. These findings were found to be conserved in human HER2 positive patients. Patients with high E2F1 activity were shown to have worse outcomes such as relapse free survival and distant metastasis free survival. This study shows conserved mechanisms of tumor progression in human breast cancer subtypes and analogous mouse models and underlies the importance of increased research into the characterization of and comparisons between mouse and human tumors to identify which mouse models resemble each subtype of human breast cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"246 1","pages":"867 - 871"},"PeriodicalIF":0.0,"publicationDate":"2015-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72759541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-10DOI: 10.18632/ONCOSCIENCE.257
M. López-Lázaro
Cancer is, in essence, a stem cell disease. The main biological cause of cancer is that stem cells acquire DNA alterations during cell division. The more stem cell divisions a tissue accumulates over a lifetime, the higher is the risk of cancer in that tissue. This explains why cancer is diagnosed millions of times more often in some tissues than in others, and why cancer incidence increases so dramatically with age. It may also explain why taking a daily low-dose aspirin for several years reduces the risk of developing and dying from cancer. Since aspirin use reduces PGE2 levels and PGE2 fuels stem cell proliferation, aspirin may prevent cancer by restricting the division rates of stem cells. The stem cell division model of cancer may also explain why regular consumption of very hot foods and beverages increases the risk of developing esophageal cancer. Given that tissue injury activates stem cell division for repair, the thermal injury associated with this dietary habit will increase esophageal cancer risk by inducing the accumulation of stem cell divisions in the esophagus. Using these two examples, here I propose that controlling the division rates of stem cells is an essential approach to preventing cancer.
{"title":"Understanding why aspirin prevents cancer and why consuming very hot beverages and foods increases esophageal cancer risk. Controlling the division rates of stem cells is an important strategy to prevent cancer","authors":"M. López-Lázaro","doi":"10.18632/ONCOSCIENCE.257","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.257","url":null,"abstract":"Cancer is, in essence, a stem cell disease. The main biological cause of cancer is that stem cells acquire DNA alterations during cell division. The more stem cell divisions a tissue accumulates over a lifetime, the higher is the risk of cancer in that tissue. This explains why cancer is diagnosed millions of times more often in some tissues than in others, and why cancer incidence increases so dramatically with age. It may also explain why taking a daily low-dose aspirin for several years reduces the risk of developing and dying from cancer. Since aspirin use reduces PGE2 levels and PGE2 fuels stem cell proliferation, aspirin may prevent cancer by restricting the division rates of stem cells. The stem cell division model of cancer may also explain why regular consumption of very hot foods and beverages increases the risk of developing esophageal cancer. Given that tissue injury activates stem cell division for repair, the thermal injury associated with this dietary habit will increase esophageal cancer risk by inducing the accumulation of stem cell divisions in the esophagus. Using these two examples, here I propose that controlling the division rates of stem cells is an essential approach to preventing cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"28 1","pages":"849 - 856"},"PeriodicalIF":0.0,"publicationDate":"2015-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85203408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-10-20DOI: 10.18632/ONCOSCIENCE.256
A. Yoshida, J. Diehl
The CDK4 and CDK6 kinases (CDK4/6) are the first cyclin dependent kinases to be activated and initiate transition through G1 phase of the cell cycle. In response to mitogenic growth factors, the CDK4/6 kinase together with one of three D-type cyclins (D1, D2, D3) initiates G1 progression by virtue of its capacity to phosphorylate the retinoblastoma protein (RB), a bona fide tumor suppressor and Gate Keeper of cell division. Phosphorylation of RB in turn results in de-repression of E2F transcription factors thereby triggering expression of genes whose products drive S-phase entry and progression (1). Cyclin D1 dysregulation occurs in a majority of human cancers, a direct result of gene amplification or mutations that disrupt its protein degradation. CDK4 amplification or activating point mutations are also observed in select malignancies. The end result of such aberrations is elevated CDK4 catalytic function, increased cell division and decreased dependence on extracellular mitogenic growth factors for cell proliferation. These observations have contributed to significant efforts to develop selective small molecule CDK4/6 inhibitors with the hope that such entities would have significant anti-cancer benefit. PD0332991 (Palbociclib), a highly selective inhibitor of CDK4 (IC50: 0.011 μM) and CDK6 (IC50: 0.016 μM), has been shown to be highly efficacious in a variety of cell culture models with regard to its capacity to suppress cell cycle progression through inhibition of CDK4/6 kinase activity in an RB-dependent manner and it is currently being tested in clinical trials for malignancies such as mantle cell lymphoma, breast cancer, and colorectal cancer (2). While acute inhibition of CDK4/6 is associated with reversible cell cycle withdraw or quiescence, some recent investigations have provided provocative evidence that Palbociclib treatment can in fact trigger irreversible withdraw, a state referred to as senescence (3, 4, 5). However the mechanisms that determine whether Palbociclib evokes quiescence versus senescence are yet to be established. In work described by Kovatcheva et al a new molecular mechanism wherein MDM2 and ATRX determine cell fate following CDK4/6 inhibition in cancer cells derived from several distinct cancer etiologies such as well-differentiated and dedifferentiated liposarcoma (WD/DDLS), lung cancer, and glioma (6). In this work, WD/DDLS cell lines were classified based upon cell fate following Palbociclib exposure: quiescence (non-responders) versus senescence (responders). While both groups had the expected reduction in RB phosphorylation, the responders also exhibited a significant decrease in MDM2 levels after prolonged CDK4 inhibition. Importantly, the phenotype is RB dependent, but is p53 and p16INK4a-independent. The capacity of MDM2 knock down to trigger senescence from quiescent phase in a combination with Palbociclib in non-responders, provides evidence that the reduction of MDM2 is in fact causative in the respo
{"title":"CDK4/6 inhibitor: from quiescence to senescence","authors":"A. Yoshida, J. Diehl","doi":"10.18632/ONCOSCIENCE.256","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.256","url":null,"abstract":"The CDK4 and CDK6 kinases (CDK4/6) are the first cyclin dependent kinases to be activated and initiate transition through G1 phase of the cell cycle. In response to mitogenic growth factors, the CDK4/6 kinase together with one of three D-type cyclins (D1, D2, D3) initiates G1 progression by virtue of its capacity to phosphorylate the retinoblastoma protein (RB), a bona fide tumor suppressor and Gate Keeper of cell division. Phosphorylation of RB in turn results in de-repression of E2F transcription factors thereby triggering expression of genes whose products drive S-phase entry and progression (1). Cyclin D1 dysregulation occurs in a majority of human cancers, a direct result of gene amplification or mutations that disrupt its protein degradation. CDK4 amplification or activating point mutations are also observed in select malignancies. The end result of such aberrations is elevated CDK4 catalytic function, increased cell division and decreased dependence on extracellular mitogenic growth factors for cell proliferation. These observations have contributed to significant efforts to develop selective small molecule CDK4/6 inhibitors with the hope that such entities would have significant anti-cancer benefit. PD0332991 (Palbociclib), a highly selective inhibitor of CDK4 (IC50: 0.011 μM) and CDK6 (IC50: 0.016 μM), has been shown to be highly efficacious in a variety of cell culture models with regard to its capacity to suppress cell cycle progression through inhibition of CDK4/6 kinase activity in an RB-dependent manner and it is currently being tested in clinical trials for malignancies such as mantle cell lymphoma, breast cancer, and colorectal cancer (2). \u0000 \u0000While acute inhibition of CDK4/6 is associated with reversible cell cycle withdraw or quiescence, some recent investigations have provided provocative evidence that Palbociclib treatment can in fact trigger irreversible withdraw, a state referred to as senescence (3, 4, 5). However the mechanisms that determine whether Palbociclib evokes quiescence versus senescence are yet to be established. In work described by Kovatcheva et al a new molecular mechanism wherein MDM2 and ATRX determine cell fate following CDK4/6 inhibition in cancer cells derived from several distinct cancer etiologies such as well-differentiated and dedifferentiated liposarcoma (WD/DDLS), lung cancer, and glioma (6). In this work, WD/DDLS cell lines were classified based upon cell fate following Palbociclib exposure: quiescence (non-responders) versus senescence (responders). While both groups had the expected reduction in RB phosphorylation, the responders also exhibited a significant decrease in MDM2 levels after prolonged CDK4 inhibition. Importantly, the phenotype is RB dependent, but is p53 and p16INK4a-independent. The capacity of MDM2 knock down to trigger senescence from quiescent phase in a combination with Palbociclib in non-responders, provides evidence that the reduction of MDM2 is in fact causative in the respo","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"11 1","pages":"896 - 897"},"PeriodicalIF":0.0,"publicationDate":"2015-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89915379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-10-07DOI: 10.18632/ONCOSCIENCE.255
E. Marques, J. Klefström
The regulatory networks of cell polarization and polarity effector proteins have been subjects of feverish interest in the field of cell and developmental biology but many advances in the polarity research may have flown unnoticed past the radar of mainstream cancer biologist. However, recent findings suggesting important cell cycle gatekeeping functions for polarity proteins may change that. For example, PAR6 proteins interact with classical cancer driver signaling pathways, including MAPK and PI3K and moreover, PAR6 (PARD6) genes are frequently altered in various cancers. Mammalian genomes harbor three different PARD6 genes. Recent studies in breast cancer have suggested that different PARD6 genes are not only important players but may play even opposite roles during tumorigenesis.
{"title":"Par6 family proteins in cancer","authors":"E. Marques, J. Klefström","doi":"10.18632/ONCOSCIENCE.255","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.255","url":null,"abstract":"The regulatory networks of cell polarization and polarity effector proteins have been subjects of feverish interest in the field of cell and developmental biology but many advances in the polarity research may have flown unnoticed past the radar of mainstream cancer biologist. However, recent findings suggesting important cell cycle gatekeeping functions for polarity proteins may change that. For example, PAR6 proteins interact with classical cancer driver signaling pathways, including MAPK and PI3K and moreover, PAR6 (PARD6) genes are frequently altered in various cancers. Mammalian genomes harbor three different PARD6 genes. Recent studies in breast cancer have suggested that different PARD6 genes are not only important players but may play even opposite roles during tumorigenesis.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"10 1","pages":"894 - 895"},"PeriodicalIF":0.0,"publicationDate":"2015-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89389523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-10-05DOI: 10.18632/ONCOSCIENCE.254
A. Eliopoulos, S. Volarevic
Serving as the cellular factory for the biogenesis of ribosomes (the molecular machines responsible for the decoding of mRNAs to proteins), the nucleolus controls a vast array of physiological processes including cell growth and proliferation. It thus comes as no surprise that inherited and acquired abnormalities in ribosome biogenesis can lead to tumorigenesis and that changes in size and number of the nucleoli, which are assumed to reflect the rate of ribosome production, have long been recognized as feature of a large number of tumor types. To safeguard against the potentially tumorigenic effects of deregulated ribosome biogenesis, cells activate the p53 tumor suppressor by re-directing the ribosomal protein (RP) L5/RPL11/5S rRNA pre-ribosomal complex from ribosome biogenesis to HDM2 binding, alleviating its inhibitory effect over p53 [1]. However, it has long been appreciated that upon exposure of cells to distinct genotoxic agents that also perturb nucleolar structure and ribosome biogenesis, the nucleolar proteins nucleophosmin (NPM) and alternative reading frame (ARF) tumor suppressor are engaged to activate p53. Thus, oncogene-induced replication stress and genotoxic insults ensue DNA damage responses that impair the nucleolar interaction of ARF with NPM, leading to the release of ARF to the nucleoplasm where it binds HDM2 and inhibits HDM2-mediated degradation of p53 [2]. NPM is also mobilized to the nucleoplasm, although with somewhat slower kinetics, to associate with free, p53-bound or de novo synthesized HDM2 [2]. The ensuing accumulation of p53 is required for cell cycle arrest, senescence or apoptosis of damaged cells. The central role of NPM in these nucleolus-orchestrated responses is further highlighted by the fact that NPM mutations which render it cytoplasmic are associated with genomic instability and the development of hematopoietic malignancies such as acute myeloid leukemia (AML) [2]. A recent study by Kanellis et al. [3] provides novel insight into the intricate management of p53 activation upon “nucleolar stress” by identifying Tumor Progression Locus 2 (TPL2; also known as COT and MAP3K8) as a physical and functional partner of NPM. TPL2 has mostly been appreciated as a cytoplasmic kinase involved in the wiring of pro-inflammatory signal transduction [4]. Kanellis et al. have found that in malignant cells and normal fibroblasts a fraction of TPL2 resides in the nucleolus where it associates with and phosphorylates a pool of NPM molecules at Thr199. As this phosphorylation event is required for NPM ubiquitination and proteasomal degradation, TPL2 appears to participate in the maintenance of physiological levels of NPM. Upon genotoxic stress this NPM pool becomes de-phosphorylated by activated PP1β [5], stabilizes and translocates to the nucleoplasm where it sequesters HDM2 away from p53 leading to a robust p53 response (Figure (Figure1).1). Consistent with this novel TPL2 function in p53 activation, several human
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