Pub Date : 2016-05-23DOI: 10.18632/oncoscience.306
Yi-Hong Zhou, Yuanjie Hu, Liping Yu, Chao Ke, Chris Vo, Hao Hsu, Zhenzhi Li, Anne T. Di Donato, A. Chaturbedi, J. Hwang, E. Siegel, M. Linskey
De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one. A series of in vitro assays on cancerous features, and subcutaneous and intracranial xenograft-formation assays, were carried out for effects from overexpression of wild-type and variant forms of EFEMP1 in two glioma subpopulations characterized as tumor mass-forming cells (TMCs) or stem-like tumor initiating cells (STICs), where EFEMP1 showed cellcontext- dependent dual functions. One of the EFEMP1 variants was identified as the sought-after ETSP, which had a stronger tumor-suppression function in TMCs by targeting EGFR and angiogenesis, and a new tumor-suppression function in STICs by targeting NOTCH signaling and MMP2-mediated cell invasion. Therefore, ETSP may form the basis for further important research to develop a novel cancer therapy to treat many types of cancer by its tumor suppressor effect in the extracellular matrix compartment.
{"title":"Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics","authors":"Yi-Hong Zhou, Yuanjie Hu, Liping Yu, Chao Ke, Chris Vo, Hao Hsu, Zhenzhi Li, Anne T. Di Donato, A. Chaturbedi, J. Hwang, E. Siegel, M. Linskey","doi":"10.18632/oncoscience.306","DOIUrl":"https://doi.org/10.18632/oncoscience.306","url":null,"abstract":"De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one. A series of in vitro assays on cancerous features, and subcutaneous and intracranial xenograft-formation assays, were carried out for effects from overexpression of wild-type and variant forms of EFEMP1 in two glioma subpopulations characterized as tumor mass-forming cells (TMCs) or stem-like tumor initiating cells (STICs), where EFEMP1 showed cellcontext- dependent dual functions. One of the EFEMP1 variants was identified as the sought-after ETSP, which had a stronger tumor-suppression function in TMCs by targeting EGFR and angiogenesis, and a new tumor-suppression function in STICs by targeting NOTCH signaling and MMP2-mediated cell invasion. Therefore, ETSP may form the basis for further important research to develop a novel cancer therapy to treat many types of cancer by its tumor suppressor effect in the extracellular matrix compartment.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"64 1","pages":"208 - 219"},"PeriodicalIF":0.0,"publicationDate":"2016-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80383194","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 : 2016-03-04DOI: 10.18632/ONCOSCIENCE.297
Haksier Ehedego, C. Trautwein
p21 historically has been considered a tumor suppressor since first studies showed that p21−/− mice display spontaneous tumor formation after 16 months and additionally these mice are more sensitive to chemically induced carcinogenesis [1,2]. On the contrary, recently a potential function as an oncogene has been described for p21. For instance mice deficient for p53 spontaneously develop multiple tumors and an additional deletion of p21 lead to a significant reduction of thymic lymphomas [3]. This argues that the complete spectrum of p21 function during tumorigenesis is not clearly identified. The role of p21 has been further studied in the NEMOΔhepa mice model. The NF-κB pathway regulator NEMO (also known as IKKγ) has been shown to control chronic inflammation and hepatocarcinogenesis in mice. The hepatocyte specific deletion of NEMO (NEMOΔhepa), is of clinical interest as these animals develop a cascade of events which resemble the spectrum of human chronic liver disease, which leads from chronic hepatitis to liver cirrhosis and growth of hepatocellular carcinomas (HCC). Additionally, a recent study using human HCC tissue found a downregulation of NEMO in tumor tissue, further supporting the translational relevance of the NEMOΔhepa mice model [4]. The deletion of NEMO in hepatocytes triggers increased p21 expression [5,6]. In order to study the relevance of p21 overexpression for disease progression of NEMOΔhepa livers, double knockout (NEMOΔhepa/p21−/−) mice carrying a hepatocyte specific deletion for NEMO and an additional constitutional deletion for p21 were generated. Although p21 is a cell cycle inhibitor its deletion had no impact on cell proliferation in 8 week-old NEMOΔhepa/p21−/− livers compared to NEMOΔhepa livers. This result was unexpected since p21 binds to CcnE/cdk2 and CcnA/cdk2 complexes thereby preventing progression from G1- to S-phase. Very likely the loss of p21 expression is compensated by other cell cycle inhibitors such as p-p27 and p18. Despite the unchanged cell cycle activity in p21 deficient NEMOΔhepa livers, the cell cycle regulator CcnA2 and CcnE2 were overexpressed. However, recent studies discovered that ectopic overexpression of CcnA or CcnE in mouse embryonic fibroblast (MEFs) lead to an increase in DNA double strand breakage [7]. Therefore the enhanced liver injury caused by exacerbation of DNA damage in p21-deficient NEMOΔhepa mice could be explained by elevated CcnA2 and CcnE2 expression. The DNA double strand breakage was quantified by pH2AX Immunofluorescence staining. p21 is not only protective against DNA damage in the chronic liver injury model as challenging double mutant NEMOΔhepa/p21−/− mice with Lipopolysaccharide (LPS) enhanced DNA damage massively compared to NEMOΔhepa mice. After LPS administration NEMOΔhepa mice suffer from severe liver injury which is reflected in the increased alanine aminotransferase (ALT) and aspartataminotransferase (AST) serum values and apoptotic cells
{"title":"p21 in chronic and acute liver injury","authors":"Haksier Ehedego, C. Trautwein","doi":"10.18632/ONCOSCIENCE.297","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.297","url":null,"abstract":"p21 historically has been considered a tumor suppressor since first studies showed that p21−/− mice display spontaneous tumor formation after 16 months and additionally these mice are more sensitive to chemically induced carcinogenesis [1,2]. \u0000 \u0000On the contrary, recently a potential function as an oncogene has been described for p21. For instance mice deficient for p53 spontaneously develop multiple tumors and an additional deletion of p21 lead to a significant reduction of thymic lymphomas [3]. \u0000 \u0000This argues that the complete spectrum of p21 function during tumorigenesis is not clearly identified. The role of p21 has been further studied in the NEMOΔhepa mice model. The NF-κB pathway regulator NEMO (also known as IKKγ) has been shown to control chronic inflammation and hepatocarcinogenesis in mice. \u0000 \u0000The hepatocyte specific deletion of NEMO (NEMOΔhepa), is of clinical interest as these animals develop a cascade of events which resemble the spectrum of human chronic liver disease, which leads from chronic hepatitis to liver cirrhosis and growth of hepatocellular carcinomas (HCC). Additionally, a recent study using human HCC tissue found a downregulation of NEMO in tumor tissue, further supporting the translational relevance of the NEMOΔhepa mice model [4]. \u0000 \u0000The deletion of NEMO in hepatocytes triggers increased p21 expression [5,6]. In order to study the relevance of p21 overexpression for disease progression of NEMOΔhepa livers, double knockout (NEMOΔhepa/p21−/−) mice carrying a hepatocyte specific deletion for NEMO and an additional constitutional deletion for p21 were generated. \u0000 \u0000Although p21 is a cell cycle inhibitor its deletion had no impact on cell proliferation in 8 week-old NEMOΔhepa/p21−/− livers compared to NEMOΔhepa livers. This result was unexpected since p21 binds to CcnE/cdk2 and CcnA/cdk2 complexes thereby preventing progression from G1- to S-phase. Very likely the loss of p21 expression is compensated by other cell cycle inhibitors such as p-p27 and p18. \u0000 \u0000Despite the unchanged cell cycle activity in p21 deficient NEMOΔhepa livers, the cell cycle regulator CcnA2 and CcnE2 were overexpressed. However, recent studies discovered that ectopic overexpression of CcnA or CcnE in mouse embryonic fibroblast (MEFs) lead to an increase in DNA double strand breakage [7]. Therefore the enhanced liver injury caused by exacerbation of DNA damage in p21-deficient NEMOΔhepa mice could be explained by elevated CcnA2 and CcnE2 expression. The DNA double strand breakage was quantified by pH2AX Immunofluorescence staining. \u0000 \u0000p21 is not only protective against DNA damage in the chronic liver injury model as challenging double mutant NEMOΔhepa/p21−/− mice with Lipopolysaccharide (LPS) enhanced DNA damage massively compared to NEMOΔhepa mice. After LPS administration NEMOΔhepa mice suffer from severe liver injury which is reflected in the increased alanine aminotransferase (ALT) and aspartataminotransferase (AST) serum values and apoptotic cells","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"108 1","pages":"56 - 57"},"PeriodicalIF":0.0,"publicationDate":"2016-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75339693","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 : 2016-03-04DOI: 10.18632/ONCOSCIENCE.295
L. Roiz, P. Smirnoff, I. Lewin, O. Shoseyov, B. Schwartz
The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate.
{"title":"Human recombinant RNASET2: A potential anti-cancer drug","authors":"L. Roiz, P. Smirnoff, I. Lewin, O. Shoseyov, B. Schwartz","doi":"10.18632/ONCOSCIENCE.295","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.295","url":null,"abstract":"The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"48 1","pages":"71 - 84"},"PeriodicalIF":0.0,"publicationDate":"2016-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91362918","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 : 2016-03-03DOI: 10.18632/ONCOSCIENCE.294
M. Nasser, D. Ahirwar, R. Ganju
Metastasis is a major cause of mortality in Breast Cancer (BC) patients in part due to lack of clinically established targeted therapies. Among the different types of BC, triple negative BC (TNBC) (ER-, PR-, HER2-) has been associated the most with poor prognosis and survival due to early metastasis to other organs and a lack of clinically established targeted therapies. Hence, elucidating novel mechanisms that regulate metastasis would lead to the development of targeted therapies and new treatments for TNBC and metastatic breast cancers. It is now well accepted that solid tumors, including those in the breast, have an inflammatory microenvironment. Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules which has been associated with chronic inflammation, which in turn enhances the progression of various cancers [1]. We have shown that RAGE is expressed in a panel of aggressive BC cell lines and TNBC tissues [3]. High RAGE expression was also observed in lymph node and distant metastases patient samples. In addition, we observed that high RAGE expression was associated with poor prognosis in breast cancer [3]. RAGE has also been shown to play important role in various cancers including pancreatic cancer. Under hypoxic environment, RAGE was shown to interact directly to mutant KRAS and upregulate HIF1α that leads to the development of pancreatic cancer [2]. We have shown that RAGE deficiency inhibits the growth of murine breast cancer tumor cells [3]. RAGEdeficient mice have shown less chemically-induced inflammation [1]. Furthermore, we have shown that RAGE neutralizing antibody treatment significantly inhibited breast cancer metastasis in an intracardial mouse model [3]. RAGE is a multi-ligand receptor and binds to several inflammatory ligands such as advanced glycation end products (AGE), high mobility group box 1 peptide (HMGB-1), amyloid-β peptide and the S100 family of proteins. Our mechanistic investigation has revealed that RAGE mediates its functional effects in breast cancer by binding to S100A7 [3]. S100A7 is a small molecular weight calcium-binding protein [4]. Although a number of putative functions have been proposed for S100A7, its biological role, particularly in BC, remains to be defined [4]. Phylogenetic analyses have shown the mouse ancestor mS100a7a15 to be most related to human S100A7 [5]. It has been shown that mS100a7a15 is up-regulated during carcinogen-induced mammary tumorigenesis. However, the direct functional role of mS100a7a15 in disease progression is not well-characterized. We have shown that mS100a7a15 overexpression induced hyperplasia in mammary glands of these transgenic mice [5]. Upon binding to ligands, RAGE activates its downstream signaling mechanisms that augment and maintain chronic inflammatory conditions [1]. We have also shown that S100A7 enhances NF-kB activation and its nuclear translocation in TNBC cells. These features of RA
{"title":"RAGE: A novel target for breast cancer growth and metastasis","authors":"M. Nasser, D. Ahirwar, R. Ganju","doi":"10.18632/ONCOSCIENCE.294","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.294","url":null,"abstract":"Metastasis is a major cause of mortality in Breast Cancer (BC) patients in part due to lack of clinically established targeted therapies. Among the different types of BC, triple negative BC (TNBC) (ER-, PR-, HER2-) has been associated the most with poor prognosis and survival due to early metastasis to other organs and a lack of clinically established targeted therapies. Hence, elucidating novel mechanisms that regulate metastasis would lead to the development of targeted therapies and new treatments for TNBC and metastatic breast cancers. \u0000 \u0000It is now well accepted that solid tumors, including those in the breast, have an inflammatory microenvironment. Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules which has been associated with chronic inflammation, which in turn enhances the progression of various cancers [1]. We have shown that RAGE is expressed in a panel of aggressive BC cell lines and TNBC tissues [3]. High RAGE expression was also observed in lymph node and distant metastases patient samples. In addition, we observed that high RAGE expression was associated with poor prognosis in breast cancer [3]. RAGE has also been shown to play important role in various cancers including pancreatic cancer. Under hypoxic environment, RAGE was shown to interact directly to mutant KRAS and upregulate HIF1α that leads to the development of pancreatic cancer [2]. \u0000 \u0000We have shown that RAGE deficiency inhibits the growth of murine breast cancer tumor cells [3]. RAGEdeficient mice have shown less chemically-induced inflammation [1]. Furthermore, we have shown that RAGE neutralizing antibody treatment significantly inhibited breast cancer metastasis in an intracardial mouse model [3]. RAGE is a multi-ligand receptor and binds to several inflammatory ligands such as advanced glycation end products (AGE), high mobility group box 1 peptide (HMGB-1), amyloid-β peptide and the S100 family of proteins. Our mechanistic investigation has revealed that RAGE mediates its functional effects in breast cancer by binding to S100A7 [3]. S100A7 is a small molecular weight calcium-binding protein [4]. Although a number of putative functions have been proposed for S100A7, its biological role, particularly in BC, remains to be defined [4]. Phylogenetic analyses have shown the mouse ancestor mS100a7a15 to be most related to human S100A7 [5]. It has been shown that mS100a7a15 is up-regulated during carcinogen-induced mammary tumorigenesis. However, the direct functional role of mS100a7a15 in disease progression is not well-characterized. We have shown that mS100a7a15 overexpression induced hyperplasia in mammary glands of these transgenic mice [5]. Upon binding to ligands, RAGE activates its downstream signaling mechanisms that augment and maintain chronic inflammatory conditions [1]. We have also shown that S100A7 enhances NF-kB activation and its nuclear translocation in TNBC cells. These features of RA","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"2 1","pages":"52 - 53"},"PeriodicalIF":0.0,"publicationDate":"2016-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89240213","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 : 2016-03-03DOI: 10.18632/ONCOSCIENCE.296
N. Mccabe, R. Kennedy, K. Prise
The phosphatase and tensin homologue, PTEN, was identified in 1997 and later found to be frequently disrupted in multiple sporadic tumour types and targeted by germline mutations in patients with cancer predisposition syndromes such as Cowden disease [1]. The principal catalytic function of PTEN is to dephosphorylate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5) P3), which is a potent activator of 3-phosphoinositidedependent kinase (PDK) and AKT. As a consequence, loss of PTEN function leads to increased levels of PtdIns(3,4,5)P3 and activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway which stimulates cell growth and survival. Additionally, recent data demonstrate that nuclear PTEN has now been demonstrated to maintain genomic stability through regulation of RAD51, a key protein involved in double-strand break (DSB) repair and stabilisation of replication fork during replication stress [2]. These distinct functions of PTEN and associated cancer predisposing mutations, has caused great interest in PTEN as a cancer biomarker.
{"title":"The role of PTEN as a cancer biomarker","authors":"N. Mccabe, R. Kennedy, K. Prise","doi":"10.18632/ONCOSCIENCE.296","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.296","url":null,"abstract":"The phosphatase and tensin homologue, PTEN, was identified in 1997 and later found to be frequently disrupted in multiple sporadic tumour types and targeted by germline mutations in patients with cancer predisposition syndromes such as Cowden disease [1]. The principal catalytic function of PTEN is to dephosphorylate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5) P3), which is a potent activator of 3-phosphoinositidedependent kinase (PDK) and AKT. As a consequence, loss of PTEN function leads to increased levels of PtdIns(3,4,5)P3 and activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway which stimulates cell growth and survival. Additionally, recent data demonstrate that nuclear PTEN has now been demonstrated to maintain genomic stability through regulation of RAD51, a key protein involved in double-strand break (DSB) repair and stabilisation of replication fork during replication stress [2]. These distinct functions of PTEN and associated cancer predisposing mutations, has caused great interest in PTEN as a cancer biomarker.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"271 3","pages":"54 - 55"},"PeriodicalIF":0.0,"publicationDate":"2016-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91473208","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 : 2016-02-12DOI: 10.18632/ONCOSCIENCE.292
David Z. Kochan, Y. Ilnytskyy, A. Golubov, S. Deibel, R. J. McDonald, O. Kovalchuk
Evidence is mounting that circadian disruption (CD) is a potential carcinogen in breast cancer development. However, despite the growing concern, to our knowledge, no studies have attempted a genome-wide analysis of CD-induced gene expression changes in mammary tissues. Using a rodent model system, a proven photoperiod-shifting paradigm, varying degrees of CD, and Illumina sequencing, we performed an exploratory genome-wide mRNA analysis in mammary tissues. Even though our analysis did not identify any significant patterns in mRNA levels based on the degree of CD, and the majority of groups did not show changes in gene expression on a large-scale, one group (two-week chronic ZT19) displayed 196 differentially expressed genes, 51 of which have been linked to breast cancer. Through gene-specific pathway analysis, the data illustrate that CD may promote breast cancer development through downregulation of DNA repair and p53 signaling pathways, thus promoting genomic instability and cancer development. Although these results have to be interpreted with caution because only a single group illustrated drastic changes in transcript levels, they indicate that chronic CD may directly induce changes in gene expression on a large-scale with potentially malignant consequences.
{"title":"Circadian-disruption-induced gene expression changes in rodent mammary tissues","authors":"David Z. Kochan, Y. Ilnytskyy, A. Golubov, S. Deibel, R. J. McDonald, O. Kovalchuk","doi":"10.18632/ONCOSCIENCE.292","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.292","url":null,"abstract":"Evidence is mounting that circadian disruption (CD) is a potential carcinogen in breast cancer development. However, despite the growing concern, to our knowledge, no studies have attempted a genome-wide analysis of CD-induced gene expression changes in mammary tissues. Using a rodent model system, a proven photoperiod-shifting paradigm, varying degrees of CD, and Illumina sequencing, we performed an exploratory genome-wide mRNA analysis in mammary tissues. Even though our analysis did not identify any significant patterns in mRNA levels based on the degree of CD, and the majority of groups did not show changes in gene expression on a large-scale, one group (two-week chronic ZT19) displayed 196 differentially expressed genes, 51 of which have been linked to breast cancer. Through gene-specific pathway analysis, the data illustrate that CD may promote breast cancer development through downregulation of DNA repair and p53 signaling pathways, thus promoting genomic instability and cancer development. Although these results have to be interpreted with caution because only a single group illustrated drastic changes in transcript levels, they indicate that chronic CD may directly induce changes in gene expression on a large-scale with potentially malignant consequences.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"9 1","pages":"58 - 70"},"PeriodicalIF":0.0,"publicationDate":"2016-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83561296","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 : 2016-02-04DOI: 10.18632/oncoscience.291
D. Del Bufalo, F. Degrassi
[This corrects the article on p. 902 in vol. 2, PMID: 26697517.].
[这更正了第2卷第902页的文章，PMID: 26697517.]
{"title":"Erratum: Kinetochore-microtube attachments in cancer therapy","authors":"D. Del Bufalo, F. Degrassi","doi":"10.18632/oncoscience.291","DOIUrl":"https://doi.org/10.18632/oncoscience.291","url":null,"abstract":"[This corrects the article on p. 902 in vol. 2, PMID: 26697517.].","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"108 1","pages":"49 - 49"},"PeriodicalIF":0.0,"publicationDate":"2016-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79407926","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 : 2016-02-01DOI: 10.18632/ONCOSCIENCE.290
A. Nistelrooij, Ronald van Marion, K. Biermann, M. Spaander, J. Lanschot, B. Wijnhoven, W. Dinjens, I. Lijnschoten, Marieke C.H. Hogenes
Esophageal adenocarcinoma (EAC) is typically diagnosed in elderly with a median age of 68 years. The incidence of EAC has been rising over the last decades, also among young adults. The aim of the study was to investigate whether early onset EAC is a distinct molecular entity. To identify early onset EACs, the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) was searched. Twenty-eight tumors of patients aged ≤40 years were selected and matched with 27 tumors of patients aged ≥68 years. DNA was isolated from surgically resected specimen and sequenced on the Ion Torrent Personal Genome Machine with the Ion AmpliSeq Cancer Panel. No differences in mutational load between early onset and conventional EACs were observed (P=0.196). The most frequently mutated genes were TP53 (73%) and P16 (16%). Additional mutations in early onset EACs occurred exclusively in: APC, CDH1, CTNNB1, FGFR2, and STK11. In the conventional EACs additional mutations were exclusively identified in: ABL1, FBXW7, GNA11, GNAS, KRAS, MET, SMAD4, and VHL. Additional mutations besides TP53 and P16 seem to occur in different genes related to cell fate pathways for early onset EACs, while the additional mutations in conventional EACs are related to survival pathways.
{"title":"Early onset esophageal adenocarcinoma: a distinct molecular entity?","authors":"A. Nistelrooij, Ronald van Marion, K. Biermann, M. Spaander, J. Lanschot, B. Wijnhoven, W. Dinjens, I. Lijnschoten, Marieke C.H. Hogenes","doi":"10.18632/ONCOSCIENCE.290","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.290","url":null,"abstract":"Esophageal adenocarcinoma (EAC) is typically diagnosed in elderly with a median age of 68 years. The incidence of EAC has been rising over the last decades, also among young adults. The aim of the study was to investigate whether early onset EAC is a distinct molecular entity. To identify early onset EACs, the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) was searched. Twenty-eight tumors of patients aged ≤40 years were selected and matched with 27 tumors of patients aged ≥68 years. DNA was isolated from surgically resected specimen and sequenced on the Ion Torrent Personal Genome Machine with the Ion AmpliSeq Cancer Panel. No differences in mutational load between early onset and conventional EACs were observed (P=0.196). The most frequently mutated genes were TP53 (73%) and P16 (16%). Additional mutations in early onset EACs occurred exclusively in: APC, CDH1, CTNNB1, FGFR2, and STK11. In the conventional EACs additional mutations were exclusively identified in: ABL1, FBXW7, GNA11, GNAS, KRAS, MET, SMAD4, and VHL. Additional mutations besides TP53 and P16 seem to occur in different genes related to cell fate pathways for early onset EACs, while the additional mutations in conventional EACs are related to survival pathways.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"53 1","pages":"42 - 48"},"PeriodicalIF":0.0,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86375115","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 : 2016-01-30DOI: 10.18632/ONCOSCIENCE.289
Jianqing Zhang, Daniel Medina-Cleghorn, L. Bernal-Mizrachi, P. Bracci, A. Hubbard, L. Conde, J. Riby, Daniel K. Nomura, C. Skibola
Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m2; 118%, P < 0.001) compared to those with a BMI < 25 kg/m2. DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs.
{"title":"The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma","authors":"Jianqing Zhang, Daniel Medina-Cleghorn, L. Bernal-Mizrachi, P. Bracci, A. Hubbard, L. Conde, J. Riby, Daniel K. Nomura, C. Skibola","doi":"10.18632/ONCOSCIENCE.289","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.289","url":null,"abstract":"Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m2; 118%, P < 0.001) compared to those with a BMI < 25 kg/m2. DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"38 1","pages":"31 - 41"},"PeriodicalIF":0.0,"publicationDate":"2016-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81019527","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 : 2016-01-29DOI: 10.18632/ONCOSCIENCE.286
Yaowu He, B. Harrington, J. Hooper
Signaling pathways regulated by the receptor CDCP1 play central roles in promoting cancer and in mediating resistance to chemo- and targeted-therapies. In this perspective we briefly summarize these findings as well as data demonstrating poorer outcomes for several malignancies that exhibit elevated CDCP1 expression. Promising data from preclinical studies suggest that CDCP1 targeted agents, including therapeutic antibodies, could be useful in the treatment of cancer patients selected on the basis of activation of CDCP1 and its signaling partners including EGFR, HER2, Met and Src.
{"title":"New crossroads for potential therapeutic intervention in cancer - intersections between CDCP1, EGFR family members and downstream signaling pathways","authors":"Yaowu He, B. Harrington, J. Hooper","doi":"10.18632/ONCOSCIENCE.286","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.286","url":null,"abstract":"Signaling pathways regulated by the receptor CDCP1 play central roles in promoting cancer and in mediating resistance to chemo- and targeted-therapies. In this perspective we briefly summarize these findings as well as data demonstrating poorer outcomes for several malignancies that exhibit elevated CDCP1 expression. Promising data from preclinical studies suggest that CDCP1 targeted agents, including therapeutic antibodies, could be useful in the treatment of cancer patients selected on the basis of activation of CDCP1 and its signaling partners including EGFR, HER2, Met and Src.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"5 - 8"},"PeriodicalIF":0.0,"publicationDate":"2016-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82043547","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}
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