Pub Date : 2015-11-23DOI: 10.18632/ONCOSCIENCE.272
K. Dodd, A. Tee
Our understanding of angiogenic signalling has been significantly enhanced through studies of a rare genetic disorder called Tuberous Sclerosis Complex (TSC). TSC patients are predisposed to highly vascularised tumours, where renal angiomyolipomas produce high levels of vascular endothelial growth factor (VEGF) that can be readily detected. It is well established that VEGF is driven through hypoxic signalling, with the transcription factor hypoxia inducible factor-1α (HIF-1α) playing a crucial role in its expression. Early studies using cell line models of TSC uncovered that the mammalian target of rapamycin complex 1 (mTORC1) is a key mediator of HIF-1α synthesis, and highlighted the anti-angiogenic properties of mTORC1 inhibitors [1]. Herein we review our recent findings characterising mTORC1 mediated regulation of HIF-1α and discuss the clinical implications of our work. We demonstrated that mTORC1 drives HIF-1α expression via three mechanisms, promoting not only the transcription of HIF-1α mRNA via signal transducer and activator of transcription 3 (STAT3), but also its translation via both eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). This drive in HIF-1α activity downstream of mTORC1 explains why the tumours which present in TSC are so heavily vascularised, and accounts for the anti-tumorigenic properties of mTOR inhibitors used in this setting. In concordance with this, we observe a 10 fold-increase in HIF-1α transcriptional activity under hypoxia with TSC2 loss, highlighting the significant impact mTORC1 activation can have on HIF-1α. Whilst mTORC1 can promote the transcriptional activity of STAT3 through direct phosphorylation of Ser727, STAT3 is also subject to regulation from a number of different cytokines and growth factors which signal through the receptor tyrosine kinase JAK2 [2]. Both JAK2/STAT3 and mTORC1 signalling pathways are frequently activated in a wide range of malignancies and converge at the level of HIF-1α (see Figure Figure1).1). Whilst mTOR inhibitors are effective at blocking Ser727 phosphorylation of STAT3, we were able to completely abolish HIF-1α expression by targeting both the JAK2-mediated Tyr705 phosphorylation site and the mTORC1-mediated Ser727 site. Our work indicates that targeting STAT3 in parallel to mTORC1 could enhance the anti-angiogenic and anti-tumorigenic properties of mTOR inhibitors that are currently in clinical use [3]. Figure 1 Multifaceted regulation of HIF-1α/VEGF-A via mTORC1 and STAT3 Growth of tumours in renal cell carcinoma (RCC) is highly dependent on mTORC1, HIF and VEGF which drive a pro-angiogenic response. In the microenvironment of the kidney, angiogenic signalling is crucial for metabolic transformation and malignancy. Although there has been much investment into drug discovery and the development of inhibitors that directly inhibit HIF, none of these compounds are currently suitable for clinical use. C
{"title":"STAT3 and mTOR: co-operating to drive HIF and angiogenesis","authors":"K. Dodd, A. Tee","doi":"10.18632/ONCOSCIENCE.272","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.272","url":null,"abstract":"Our understanding of angiogenic signalling has been significantly enhanced through studies of a rare genetic disorder called Tuberous Sclerosis Complex (TSC). TSC patients are predisposed to highly vascularised tumours, where renal angiomyolipomas produce high levels of vascular endothelial growth factor (VEGF) that can be readily detected. It is well established that VEGF is driven through hypoxic signalling, with the transcription factor hypoxia inducible factor-1α (HIF-1α) playing a crucial role in its expression. Early studies using cell line models of TSC uncovered that the mammalian target of rapamycin complex 1 (mTORC1) is a key mediator of HIF-1α synthesis, and highlighted the anti-angiogenic properties of mTORC1 inhibitors [1]. Herein we review our recent findings characterising mTORC1 mediated regulation of HIF-1α and discuss the clinical implications of our work. \u0000 \u0000We demonstrated that mTORC1 drives HIF-1α expression via three mechanisms, promoting not only the transcription of HIF-1α mRNA via signal transducer and activator of transcription 3 (STAT3), but also its translation via both eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). This drive in HIF-1α activity downstream of mTORC1 explains why the tumours which present in TSC are so heavily vascularised, and accounts for the anti-tumorigenic properties of mTOR inhibitors used in this setting. In concordance with this, we observe a 10 fold-increase in HIF-1α transcriptional activity under hypoxia with TSC2 loss, highlighting the significant impact mTORC1 activation can have on HIF-1α. \u0000 \u0000Whilst mTORC1 can promote the transcriptional activity of STAT3 through direct phosphorylation of Ser727, STAT3 is also subject to regulation from a number of different cytokines and growth factors which signal through the receptor tyrosine kinase JAK2 [2]. Both JAK2/STAT3 and mTORC1 signalling pathways are frequently activated in a wide range of malignancies and converge at the level of HIF-1α (see Figure Figure1).1). Whilst mTOR inhibitors are effective at blocking Ser727 phosphorylation of STAT3, we were able to completely abolish HIF-1α expression by targeting both the JAK2-mediated Tyr705 phosphorylation site and the mTORC1-mediated Ser727 site. Our work indicates that targeting STAT3 in parallel to mTORC1 could enhance the anti-angiogenic and anti-tumorigenic properties of mTOR inhibitors that are currently in clinical use [3]. \u0000 \u0000 \u0000 \u0000Figure 1 \u0000 \u0000Multifaceted regulation of HIF-1α/VEGF-A via mTORC1 and STAT3 \u0000 \u0000 \u0000 \u0000Growth of tumours in renal cell carcinoma (RCC) is highly dependent on mTORC1, HIF and VEGF which drive a pro-angiogenic response. In the microenvironment of the kidney, angiogenic signalling is crucial for metabolic transformation and malignancy. Although there has been much investment into drug discovery and the development of inhibitors that directly inhibit HIF, none of these compounds are currently suitable for clinical use. C","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"44 1","pages":"913 - 914"},"PeriodicalIF":0.0,"publicationDate":"2015-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90582742","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 : 2015-11-23DOI: 10.18632/ONCOSCIENCE.273
K. Yoon, A. Miller, K. Kreitzburg
The role of immunoglobulin superfamily cell adhesion molecules (CAMs) in facilitating immune responses in normal and tumor cells is well established. Cell adhesion molecule-1 (CADM1), for example, suppresses development of mouse mammary tumor cell metastasis by interacting with CD8+ T cells in immune-competent hosts [1]. Similarly, co-expression of Intercellular Adhesion Molecule-2 (ICAM-2) and chemokine C-X-C motif ligand 17 (CXCL17) elicits anti-tumor immune responses and suppresses tumor growth [2]. Although controversial, current literature suggests that proteins of the immunoglobulin superfamily CAMs also have functions that may well be distinct from their roles in mediating immune responses. Junctional adhesion molecule-A (JAM-A), for example, negatively regulates breast cancer cell invasiveness by disrupting tight junctions [3]; and a member of the B7 family of the immunoglobulin superfamily proteins, B7-H3, impairs osteogenic differentiation in vitro and in vivo [4]. Our lab demonstrated that ICAM-2 inhibited the development of disseminated neuroblastoma tumors in a preclinical model of metastatic neuroblastoma [5-7]. This inhibition depended on the interaction of ICAM-2 with the actin cytoskeletal linker protein α-actinin, an interaction that inhibited cell motility [7]. Ectopic expression of ICAM-2 did not affect the tumorigenic potential of neuroblastoma cells [7]. Importantly, immunohistochemical analyses of primary neuroblastoma tumor specimens demonstrated that neuroblastoma cells expressing ICAM-2 are phenotypically and histologically those recognized clinically to have limited metastatic potential [5]. Since metastatic disease is responsible for >90% of cancer-related deaths for multiple types of solid tumors, we suggest that elucidation of the molecular mechanism by which ICAM-2 suppresses the metastatic potential of neuroblastoma cells would identify proteins or pathways that might be exploited therapeutically to prevent metastatic disease progression. In normal tissues ICAM-2 is expressed predominantly by neovascular endothelial cells, and at lower levels by established vasculature and some leukocytes. The 202 amino acids comprising its extracellular domain mediate binding of ICAM-2 on endothelial cells to β2-integrins on the surface of leukocytes, to facilitate migration of neutrophils through the vascular endothelium as a component of immune reactions [8]. In neuroblastoma cells ICAM-2 inhibits cell motility independent of immune response, as we observed this inhibition in wound healing and modified Boyden chamber assays in vitro, assays that clearly lack an immune component [5,7]. In silico modeling indicated that ICAM-2 with mutations in the proposed α-actinin binding domain had a more ‘closed’ configuration than the wild type protein, and predicted that these ICAM-2 mutants would not interact with α-actinin [7]. Co-immunoprecipitation experiments confirmed in silico predictions [7]. In support of these findings, t
免疫球蛋白超家族细胞粘附分子(CAMs)在促进正常细胞和肿瘤细胞免疫应答中的作用已经得到了很好的证实。例如，细胞粘附分子-1 (CADM1)通过与免疫活性宿主中的CD8+ T细胞相互作用，抑制小鼠乳腺肿瘤细胞转移的发展[1]。同样，细胞间粘附分子-2 (ICAM-2)和趋化因子C-X-C基序配体17 (CXCL17)的共表达引发抗肿瘤免疫反应并抑制肿瘤生长[2]。尽管存在争议，但目前的文献表明，免疫球蛋白超家族CAMs的蛋白质也具有与其介导免疫反应的作用截然不同的功能。例如，连接粘附分子- a (JAM-A)通过破坏紧密连接来负向调节乳腺癌细胞的侵袭性[3];以及免疫球蛋白超家族蛋白B7家族的成员B7- h3，在体外和体内都能阻碍成骨分化[4]。我们的实验室在转移性神经母细胞瘤临床前模型中证实，ICAM-2抑制播散性神经母细胞瘤肿瘤的发展[5-7]。这种抑制依赖于ICAM-2与肌动蛋白细胞骨架连接蛋白α-肌动蛋白的相互作用，这种相互作用抑制细胞运动[7]。异位表达ICAM-2不影响神经母细胞瘤细胞的致瘤潜能[7]。重要的是，原发性神经母细胞瘤肿瘤标本的免疫组织化学分析表明，在表型和组织学上表达ICAM-2的神经母细胞瘤细胞在临床上被认为具有有限的转移潜力[5]。由于转移性疾病是多种类型实体肿瘤中90%以上的癌症相关死亡的原因，我们建议阐明ICAM-2抑制神经母细胞瘤细胞转移潜能的分子机制，从而确定可能用于治疗预防转移性疾病进展的蛋白质或途径。在正常组织中，ICAM-2主要由新生血管内皮细胞表达，在已建立的血管和一些白细胞中表达的水平较低。其胞外结构域由202个氨基酸组成，介导内皮细胞上的ICAM-2与白细胞表面的β2整合素结合，促进中性粒细胞通过血管内皮迁移，作为免疫反应的一个组成部分[8]。在神经母细胞瘤细胞中，ICAM-2抑制独立于免疫反应的细胞运动，正如我们在体外伤口愈合和改良Boyden室实验中观察到的那样，这种抑制作用显然缺乏免疫成分[5,7]。计算机模拟表明，在α-肌动蛋白结合区域发生突变的ICAM-2比野生型蛋白具有更“封闭”的结构，并预测这些ICAM-2突变体不会与α-肌动蛋白相互作用[7]。共免疫沉淀实验证实了计算机预测[7]。为了支持这些发现，ICAM-2与α-肌动蛋白的相互作用对于抑制体内播散性肿瘤的发展至关重要[7]。如前所述，ICAM-2不影响致瘤潜力，未发表的数据显示ICAM-2对上皮-间质转化(EMT)或干性标志物的表达没有影响。尽管我们认为ICAM-2在体外抑制肿瘤细胞运动是ICAM-2参与不同于免疫反应的细胞功能的有力证据，但我们承认转移性肿瘤进展的复杂性，并提出我们的数据提出了关于ICAM-2抑制神经母细胞瘤细胞运动的机制的多种假设。第一种假设是，ICAM-2与α-肌动蛋白的细胞内相互作用启动了“由内到外”的信号传导，并导致ICAM-2的细胞外结构域的构象变化，从而促进(或抑制)与特定的细胞外基质蛋白的相互作用，这些蛋白在细胞运动中起着不可或缺的作用。其次，ICAM-2与α-肌动蛋白的相互作用改变了α-肌动蛋白的构象，促进(或抑制)这种肌动蛋白细胞骨架蛋白与其他结合伙伴的结合，ICAM-2充当α-肌动蛋白的“激活剂”(或抑制剂)，而不是作为膜锚蛋白。基于未发表的微阵列数据的第三种假设是，ICAM-2表达间接上调参与局灶黏附形成和维持的蛋白酪氨酸磷酸酶(PTPs)，如局灶黏附激酶(FAK)、Src或Rac和Rho GTPases，它们在肿瘤细胞运动中都起着至关重要的作用。我们的数据显示，ICAM-2抑制肿瘤细胞的运动和抑制神经母细胞瘤细胞的转移潜能。我们建议阐明与ICAM-2表达相关的分子事件将确定调节这种细胞类型转移过程的关键蛋白相互作用。
{"title":"The role of ICAM-2 in neuroblastoma","authors":"K. Yoon, A. Miller, K. Kreitzburg","doi":"10.18632/ONCOSCIENCE.273","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.273","url":null,"abstract":"The role of immunoglobulin superfamily cell adhesion molecules (CAMs) in facilitating immune responses in normal and tumor cells is well established. Cell adhesion molecule-1 (CADM1), for example, suppresses development of mouse mammary tumor cell metastasis by interacting with CD8+ T cells in immune-competent hosts [1]. Similarly, co-expression of Intercellular Adhesion Molecule-2 (ICAM-2) and chemokine C-X-C motif ligand 17 (CXCL17) elicits anti-tumor immune responses and suppresses tumor growth [2]. Although controversial, current literature suggests that proteins of the immunoglobulin superfamily CAMs also have functions that may well be distinct from their roles in mediating immune responses. Junctional adhesion molecule-A (JAM-A), for example, negatively regulates breast cancer cell invasiveness by disrupting tight junctions [3]; and a member of the B7 family of the immunoglobulin superfamily proteins, B7-H3, impairs osteogenic differentiation in vitro and in vivo [4]. \u0000 \u0000Our lab demonstrated that ICAM-2 inhibited the development of disseminated neuroblastoma tumors in a preclinical model of metastatic neuroblastoma [5-7]. This inhibition depended on the interaction of ICAM-2 with the actin cytoskeletal linker protein α-actinin, an interaction that inhibited cell motility [7]. Ectopic expression of ICAM-2 did not affect the tumorigenic potential of neuroblastoma cells [7]. Importantly, immunohistochemical analyses of primary neuroblastoma tumor specimens demonstrated that neuroblastoma cells expressing ICAM-2 are phenotypically and histologically those recognized clinically to have limited metastatic potential [5]. Since metastatic disease is responsible for >90% of cancer-related deaths for multiple types of solid tumors, we suggest that elucidation of the molecular mechanism by which ICAM-2 suppresses the metastatic potential of neuroblastoma cells would identify proteins or pathways that might be exploited therapeutically to prevent metastatic disease progression. \u0000 \u0000In normal tissues ICAM-2 is expressed predominantly by neovascular endothelial cells, and at lower levels by established vasculature and some leukocytes. The 202 amino acids comprising its extracellular domain mediate binding of ICAM-2 on endothelial cells to β2-integrins on the surface of leukocytes, to facilitate migration of neutrophils through the vascular endothelium as a component of immune reactions [8]. In neuroblastoma cells ICAM-2 inhibits cell motility independent of immune response, as we observed this inhibition in wound healing and modified Boyden chamber assays in vitro, assays that clearly lack an immune component [5,7]. \u0000 \u0000In silico modeling indicated that ICAM-2 with mutations in the proposed α-actinin binding domain had a more ‘closed’ configuration than the wild type protein, and predicted that these ICAM-2 mutants would not interact with α-actinin [7]. Co-immunoprecipitation experiments confirmed in silico predictions [7]. In support of these findings, t","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"17 1","pages":"915 - 916"},"PeriodicalIF":0.0,"publicationDate":"2015-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87665668","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 : 2015-11-21DOI: 10.18632/ONCOSCIENCE.270
Sarah R Walker, D. Frank
Breast cancer remains the second leading cause of cancer deaths in women in the United States. Triple negative breast cancer, tumors lacking estrogen receptor, progesterone receptor, and Her2, only comprise about 20–30% of breast tumors diagnosed. However, due to the lack of specific targeted therapy as exists for ER+ or Her2+ tumors, they account for many of the breast cancer deaths. To develop targeted therapy for triple negative breast cancer, inhibiting two targets may be necessary. One new target of interest is the transcriptional modulator BCL6 which has been recently identified as playing an important role in breast cancer [1–3]. BCL6 has been characterized as a transcriptional repressor that recruits various corepressor complexes to repress its target genes; however, genes have also been identified that are upregulated by BCL6 [1, 2], including Zeb1 which is involved in promoting EMT [3]. While the roles of BCL6 in preventing terminal differentiation of B cells in the germinal center and promoting diffuse large B cell lymphoma are well known, little is currently known about the roles of BCL6 in solid tissue. BCL6 is amplified in ∼50% of breast tumors and is expressed in most breast cancer cell lines, including triple negative breast cancer cell lines [1]. Furthermore, BCL6 expression is correlated with disease progression and poor overall survival [2], and targeting BCL6 results in reduced growth and loss of breast cancer cell viability [1]. Importantly, triple negative breast cancer cell lines were among the most sensitive to BCL6 inhibition. In the normal mammary gland, BCL6 has been shown to prevent terminal differentiation and milk production, in part due to competition with signal transducer and activator of transcription 5 (STAT5) for regulation of target genes [4]. STATs are latent transcription factors that remain in the cytoplasm until activated by tyrosine phosphorylation often via Jak kinases. They then translocate to the nucleus as an active dimer and modulate transcription of target genes. There are seven members of the STAT family and four members, STAT1, STAT3, STAT5a, and STAT5b regulate the expression of BCL6. While STAT1 and STAT3 upregulate BCL6 expression, STAT5 (5a and 5b) downregulates BCL6 expression [5]. All four STATs have been shown to play roles in breast cancer; however, STAT3 activation has been linked to more aggressive types. While STAT3 activation can occur in any subtype of breast cancer [5], STAT3 activation is restricted largely to triple negative breast cancer cell lines, and STAT3 signaling has been shown to be important for the survival of triple negative breast tumors [6]. Both BCL6 and STAT3 play critical roles in triple negative breast cancer, including promoting survival and EMT, through modulating largely distinct target genes. Thus, could targeting these two factors together be a useful strategy for specifically treating triple negative breast cancer? Inhibition of BCL6 by siRNA or the
{"title":"Targeting BCL6 and STAT3 in triple negative breast cancer: the one-two punch?","authors":"Sarah R Walker, D. Frank","doi":"10.18632/ONCOSCIENCE.270","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.270","url":null,"abstract":"Breast cancer remains the second leading cause of cancer deaths in women in the United States. Triple negative breast cancer, tumors lacking estrogen receptor, progesterone receptor, and Her2, only comprise about 20–30% of breast tumors diagnosed. However, due to the lack of specific targeted therapy as exists for ER+ or Her2+ tumors, they account for many of the breast cancer deaths. To develop targeted therapy for triple negative breast cancer, inhibiting two targets may be necessary. \u0000 \u0000One new target of interest is the transcriptional modulator BCL6 which has been recently identified as playing an important role in breast cancer [1–3]. BCL6 has been characterized as a transcriptional repressor that recruits various corepressor complexes to repress its target genes; however, genes have also been identified that are upregulated by BCL6 [1, 2], including Zeb1 which is involved in promoting EMT [3]. While the roles of BCL6 in preventing terminal differentiation of B cells in the germinal center and promoting diffuse large B cell lymphoma are well known, little is currently known about the roles of BCL6 in solid tissue. BCL6 is amplified in ∼50% of breast tumors and is expressed in most breast cancer cell lines, including triple negative breast cancer cell lines [1]. Furthermore, BCL6 expression is correlated with disease progression and poor overall survival [2], and targeting BCL6 results in reduced growth and loss of breast cancer cell viability [1]. Importantly, triple negative breast cancer cell lines were among the most sensitive to BCL6 inhibition. In the normal mammary gland, BCL6 has been shown to prevent terminal differentiation and milk production, in part due to competition with signal transducer and activator of transcription 5 (STAT5) for regulation of target genes [4]. \u0000 \u0000STATs are latent transcription factors that remain in the cytoplasm until activated by tyrosine phosphorylation often via Jak kinases. They then translocate to the nucleus as an active dimer and modulate transcription of target genes. There are seven members of the STAT family and four members, STAT1, STAT3, STAT5a, and STAT5b regulate the expression of BCL6. While STAT1 and STAT3 upregulate BCL6 expression, STAT5 (5a and 5b) downregulates BCL6 expression [5]. All four STATs have been shown to play roles in breast cancer; however, STAT3 activation has been linked to more aggressive types. While STAT3 activation can occur in any subtype of breast cancer [5], STAT3 activation is restricted largely to triple negative breast cancer cell lines, and STAT3 signaling has been shown to be important for the survival of triple negative breast tumors [6]. \u0000 \u0000Both BCL6 and STAT3 play critical roles in triple negative breast cancer, including promoting survival and EMT, through modulating largely distinct target genes. Thus, could targeting these two factors together be a useful strategy for specifically treating triple negative breast cancer? Inhibition of BCL6 by siRNA or the ","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"79 1","pages":"912 - 912"},"PeriodicalIF":0.0,"publicationDate":"2015-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82403705","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 : 2015-11-20DOI: 10.18632/ONCOSCIENCE.271
D. Bonci, R. De Maria
Prostate cancer remains the second leading cause of death in men. It is imperative to improve patient management in identifying bio-markers for personalized treatment. We demonstrated miR-15/miR-16 loss and miR-21 up-regulation and deregulation of their target genes, which represent a promising signature for ameliorating therapy assignment and risk assessment in prostate cancer.
{"title":"A predictive signature for therapy assignment and risk assessment in prostate cancer","authors":"D. Bonci, R. De Maria","doi":"10.18632/ONCOSCIENCE.271","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.271","url":null,"abstract":"Prostate cancer remains the second leading cause of death in men. It is imperative to improve patient management in identifying bio-markers for personalized treatment. We demonstrated miR-15/miR-16 loss and miR-21 up-regulation and deregulation of their target genes, which represent a promising signature for ameliorating therapy assignment and risk assessment in prostate cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"8 1","pages":"920 - 923"},"PeriodicalIF":0.0,"publicationDate":"2015-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86955882","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 : 2015-11-19DOI: 10.18632/ONCOSCIENCE.269
Siqi Chen, Yi Zhang, Bin Zhang
MicroRNA is small non-coding RNA and can lead to translational repression or target degradation by base-pairing with complementary sequences of mRNA molecules. MicroRNA-155 (miR-155), one of the most studied microRNA, is the first one to be reported as oncogenic [1]. miR-155 is over expressed in a long list of both hematological and solid tumors and is of paramount importance in cancer diagnosis and prognosis. However, how miR-155 particularly in host immune system regulates the tumor progression remains poorly understood. Our study underscores a contextual role of miR-155 in regulating tumor growth and tumor immunity via distinct immune subsets within tumors [2]. We conclude that the balance of different effects between those immune cell populations, which are regulated by miR-155, appears to determine whether miR-155 promotes or inhibits tumor growth [2]. We demonstrated that host miR-155 deficiency promoted antitumor T cell immunity in multiple transplanted tumor models. Further analysis of immune cell compartments revealed that miR-155 was required for the accumulation and suppressive function of myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Apart from the direct modulation on MDSC, miR-155 was also required for the MDSC-mediated CD4+Foxp3+ regulatory T cells (Treg) induction. On the other hand, miR-155 deficiency hampered the antitumor responses of both dendritic cells and T cells. Therefore, it appears that in our tumor models, miR-155 mediated a dominant immunosuppressive effect by MDSC, leading to the enhanced overall antitumor immunity in miR-155 deficient hosts. Reduced colon inflammation and decreased colorectal carcinogenesis were also found in miR-155 deficient mice when azoxymethane (AOM) and dextran sodium sulphate (DSS) were combined to induce colon lesions. Furthermore, miR-155 was upregulated in MDSC either from tumor-bearing hosts or generated from bone marrow progenitors by GM-CSF and IL-6. These results support the notion that miR-155 is a prototypical microRNA bridging inflammation and cancer development [3]. Although miR-155 may regulate tumor growth in an intrinsic manner, it is likely that inflammation promotes the accumulation of functional MDSC by increased miR-155 that dampens the immune surveillance and antitumor immunity, thereby facilitating tumor growth. To identify the molecular mechanisms by which miR-155 regulates MDSC (Figure (Figure1),1), we found that miR155 retained the suppressive activity of MDSCs through inhibiting SOCS1. Moreover, inverse correlations between miR-155 expression and SHIP-1/SOCS1 expression were established in MDSC. As SHIP-1 was recently reported as a target of miR155 specifically in MDSC expansion [4], these results suggest both SHIP-1 and SOCS1 as target genes of miR-155 during functional MDSC generation. SOCS1 also restricted arginase I activity [5], which otherwise would limit the efficiency of MDSC proinflammatory responses. Indeed, we showed that
{"title":"MicroRNA-155 regulates tumor myeloid-derived suppressive cells","authors":"Siqi Chen, Yi Zhang, Bin Zhang","doi":"10.18632/ONCOSCIENCE.269","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.269","url":null,"abstract":"MicroRNA is small non-coding RNA and can lead to translational repression or target degradation by base-pairing with complementary sequences of mRNA molecules. MicroRNA-155 (miR-155), one of the most studied microRNA, is the first one to be reported as oncogenic [1]. miR-155 is over expressed in a long list of both hematological and solid tumors and is of paramount importance in cancer diagnosis and prognosis. However, how miR-155 particularly in host immune system regulates the tumor progression remains poorly understood. Our study underscores a contextual role of miR-155 in regulating tumor growth and tumor immunity via distinct immune subsets within tumors [2]. We conclude that the balance of different effects between those immune cell populations, which are regulated by miR-155, appears to determine whether miR-155 promotes or inhibits tumor growth [2]. \u0000 \u0000We demonstrated that host miR-155 deficiency promoted antitumor T cell immunity in multiple transplanted tumor models. Further analysis of immune cell compartments revealed that miR-155 was required for the accumulation and suppressive function of myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Apart from the direct modulation on MDSC, miR-155 was also required for the MDSC-mediated CD4+Foxp3+ regulatory T cells (Treg) induction. On the other hand, miR-155 deficiency hampered the antitumor responses of both dendritic cells and T cells. Therefore, it appears that in our tumor models, miR-155 mediated a dominant immunosuppressive effect by MDSC, leading to the enhanced overall antitumor immunity in miR-155 deficient hosts. \u0000 \u0000Reduced colon inflammation and decreased colorectal carcinogenesis were also found in miR-155 deficient mice when azoxymethane (AOM) and dextran sodium sulphate (DSS) were combined to induce colon lesions. Furthermore, miR-155 was upregulated in MDSC either from tumor-bearing hosts or generated from bone marrow progenitors by GM-CSF and IL-6. These results support the notion that miR-155 is a prototypical microRNA bridging inflammation and cancer development [3]. Although miR-155 may regulate tumor growth in an intrinsic manner, it is likely that inflammation promotes the accumulation of functional MDSC by increased miR-155 that dampens the immune surveillance and antitumor immunity, thereby facilitating tumor growth. \u0000 \u0000To identify the molecular mechanisms by which miR-155 regulates MDSC (Figure (Figure1),1), we found that miR155 retained the suppressive activity of MDSCs through inhibiting SOCS1. Moreover, inverse correlations between miR-155 expression and SHIP-1/SOCS1 expression were established in MDSC. As SHIP-1 was recently reported as a target of miR155 specifically in MDSC expansion [4], these results suggest both SHIP-1 and SOCS1 as target genes of miR-155 during functional MDSC generation. SOCS1 also restricted arginase I activity [5], which otherwise would limit the efficiency of MDSC proinflammatory responses. Indeed, we showed that ","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"21 1","pages":"910 - 911"},"PeriodicalIF":0.0,"publicationDate":"2015-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89357128","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 : 2015-11-19DOI: 10.18632/ONCOSCIENCE.268
A. Udager, J. Mchugh, K. Elenitoba-Johnson, N. Brown
Sinonasal squamous cell carcinoma (SNSCC) and sinonasal papillomas constitute a diverse group of epithelial tumors arising in the sinonasal tract [1]. Sinonasal papillomas are benign tumors classified into three distinct histologic types: exophytic (fungiform), inverted, and oncocytic. While exophytic sinonasal papillomas (ESP) arise from the nasal septum and are only rarely associated with SNSCC, inverted sinonasal papillomas (ISP) and oncocytic sinonasal papillomas (OSP) typically arise from the lateral portion of the nasal cavity and are more frequently associated with synchronous or metachronous SNSCC – up to 25%, depending on the study [2]. The etiology of sinonasal tumors is a topic of current debate [1]. While ESP is associated with infection by low-risk human papillomavirus (HPV) in 55% - 65% [1, 3], most studies have demonstrated significantly lower HPV detections rates for ISP [3, 4]. Similarly, less than half of SNSCC are associated with HPV infection [3, 4] and the incidence in SNSCC associated with ISP may be even lower [5]. These data suggest that while HPV infection may play a role in the pathogenesis of a subset of these tumors, it is not the only factor involved in SNP and SNSCC oncogenesis. In a recent study, our group identified activating somatic EGFR mutations in 88% of ISP and 77% of SNSCC associated with ISP [6]. Importantly, while a variety of different EGFR mutations were found in these tumors, concordant EGFR genotypes were identified for all matched pairs of ISP and synchronous or metachronous SNSCC. Therefore, this study provided the first molecular evidence to support the role of ISP as a precursor lesion for SNSCC. In addition, EGFR mutation status was a significant prognostic factor for ISP, with EGFR wild-type tumors showing earlier progression to SNSCC. No EGFR mutations were identified in ESP, OSP, or SNSCC not associated with ISP, suggesting that the ISP/SNSCC disease spectrum is biologically distinct from these other sinonasal squamous tumors. The oncogenic role of EGFR mutations was supported in this study by functional experiments. In cell lines derived from ISP-associated SNSCC, EGFR mutations were shown to result in activation of EGFR as well as downstream constituents of the MAPK and PI3K/AKT/mTOR signaling pathways. Taken together, these functional studies and the high frequency of EGFR mutations suggest that dysregulated EGFR signaling plays a central role in the oncogenesis of ISP and associated SNSCC – a finding that is an apparent departure from prior paradigms involving HPV infection [1]. These findings, however, do not strictly preclude a role for HPV in these tumors. The HPV-associated E5 oncoprotein has been shown to inhibit EGFR degradation, alter endosomal trafficking of EGFR and activate proteins downstream of EGFR in a ligand-independent manner [7] (Figure (Figure1).1). Thus, it is plausible that altered EGFR signaling itself – either as a result of somatic activating EGFR mutations
{"title":"EGFR mutations in sinonasal squamous tumors: oncogenic and therapeutic implications","authors":"A. Udager, J. Mchugh, K. Elenitoba-Johnson, N. Brown","doi":"10.18632/ONCOSCIENCE.268","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.268","url":null,"abstract":"Sinonasal squamous cell carcinoma (SNSCC) and sinonasal papillomas constitute a diverse group of epithelial tumors arising in the sinonasal tract [1]. Sinonasal papillomas are benign tumors classified into three distinct histologic types: exophytic (fungiform), inverted, and oncocytic. While exophytic sinonasal papillomas (ESP) arise from the nasal septum and are only rarely associated with SNSCC, inverted sinonasal papillomas (ISP) and oncocytic sinonasal papillomas (OSP) typically arise from the lateral portion of the nasal cavity and are more frequently associated with synchronous or metachronous SNSCC – up to 25%, depending on the study [2]. \u0000 \u0000The etiology of sinonasal tumors is a topic of current debate [1]. While ESP is associated with infection by low-risk human papillomavirus (HPV) in 55% - 65% [1, 3], most studies have demonstrated significantly lower HPV detections rates for ISP [3, 4]. Similarly, less than half of SNSCC are associated with HPV infection [3, 4] and the incidence in SNSCC associated with ISP may be even lower [5]. These data suggest that while HPV infection may play a role in the pathogenesis of a subset of these tumors, it is not the only factor involved in SNP and SNSCC oncogenesis. \u0000 \u0000In a recent study, our group identified activating somatic EGFR mutations in 88% of ISP and 77% of SNSCC associated with ISP [6]. Importantly, while a variety of different EGFR mutations were found in these tumors, concordant EGFR genotypes were identified for all matched pairs of ISP and synchronous or metachronous SNSCC. Therefore, this study provided the first molecular evidence to support the role of ISP as a precursor lesion for SNSCC. In addition, EGFR mutation status was a significant prognostic factor for ISP, with EGFR wild-type tumors showing earlier progression to SNSCC. No EGFR mutations were identified in ESP, OSP, or SNSCC not associated with ISP, suggesting that the ISP/SNSCC disease spectrum is biologically distinct from these other sinonasal squamous tumors. \u0000 \u0000The oncogenic role of EGFR mutations was supported in this study by functional experiments. In cell lines derived from ISP-associated SNSCC, EGFR mutations were shown to result in activation of EGFR as well as downstream constituents of the MAPK and PI3K/AKT/mTOR signaling pathways. Taken together, these functional studies and the high frequency of EGFR mutations suggest that dysregulated EGFR signaling plays a central role in the oncogenesis of ISP and associated SNSCC – a finding that is an apparent departure from prior paradigms involving HPV infection [1]. These findings, however, do not strictly preclude a role for HPV in these tumors. The HPV-associated E5 oncoprotein has been shown to inhibit EGFR degradation, alter endosomal trafficking of EGFR and activate proteins downstream of EGFR in a ligand-independent manner [7] (Figure (Figure1).1). Thus, it is plausible that altered EGFR signaling itself – either as a result of somatic activating EGFR mutations ","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"7 1","pages":"908 - 909"},"PeriodicalIF":0.0,"publicationDate":"2015-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78435473","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 : 2015-11-18DOI: 10.18632/ONCOSCIENCE.267
Sandra Healy, L. O’Leary, E. Szegezdi
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF cytokine family and a selective inducer of apoptosis in a range of tumour cells, but not in healthy normal, untransformed cells. It is expressed by natural killer cells and natural killer-T cells when they encounter malignantly transformed cells and it is a key effector molecule in tumour immune surveillance. TRAIL has 5 receptors, which is the highest receptor promiscuity in the TNF ligand family. It binds to death receptor 4 (DR4) or DR5 on the surface of target cells [1] and initiates a conformational change which promotes association of the receptors with FADD facilitating pro-caspase-8 and/or pro-caspase-10 recruitment which then activates effector caspases to execute cell death [2]. Signalling through DR4 and DR5 can also activate pro-inflammatory intracellular molecules such as MAPK, PKB and NF-κB and overexpression of DR4 or DR5 has been shown to stimulate the release of inflammatory cytokines [3]. However, TRAIL also has three regulatory receptors. Two of these, decoy receptor 1(DcR1) and DcR2 are membrane bound and the third regulatory receptor, osteoprotegerin is a secreted protein. DcRs regulate TRAIL-induced apoptosis by either sequestering TRAIL from the death receptors or by forming inactive, heteromeric DcR1/2–DR4/5 complexes [1]. Indeed, DcRs have been shown to be highly expressed in a number of tumour tissues such as acute myeloid leukaemia, prostate cancer and breast cancer and their expression is linked with poor prognosis [4]. However DcR expression in tumour cells does not correlate with TRAIL sensitivity and non-transformed cells do not require DcRs to be protected from TRAIL-induced apoptosis, suggesting that the in vivo role of the DcRs may be more complex than originally thought [5] The tumor-specific cytotoxicity of TRAIL has been exploited as a therapeutic strategy by utilizing recombinant versions of TRAIL and agonistic antibodies against DR4 and DR5 [6]. While recombinant soluble human TRAIL was highly potent against a broad range of tumours in vitro and in pre-clinical studies, in clinical trials TRAIL has failed to exhibit the same potency [6]. One of the major shortcomings of the preclinical models was the lack of assessment of the contribution of the tumour microenvironment (TME). The TME consists of various cell types, soluble factors and signals from the extracellular matrix, and is in a reciprocal interaction with the tumour cells. It is thus important to understand the interplay of different cell types in the tumour microenvironment and the effect of the factors they express and secrete on tumour growth, development and resistance to therapy. Figure 1 Cell autonomous and supracellular regulation of TRAIL-sensitivity by decoy receptor 1 (DcR1) and -2 The study by O'Leary and colleagues explored the hypothesis that DcRs exerted a ‘supracellular level control’ of TRAIL-sensitivity rather than simply regula
{"title":"An added dimension to tumour TRAIL sensitivity","authors":"Sandra Healy, L. O’Leary, E. Szegezdi","doi":"10.18632/ONCOSCIENCE.267","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.267","url":null,"abstract":"Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF cytokine family and a selective inducer of apoptosis in a range of tumour cells, but not in healthy normal, untransformed cells. It is expressed by natural killer cells and natural killer-T cells when they encounter malignantly transformed cells and it is a key effector molecule in tumour immune surveillance. TRAIL has 5 receptors, which is the highest receptor promiscuity in the TNF ligand family. It binds to death receptor 4 (DR4) or DR5 on the surface of target cells [1] and initiates a conformational change which promotes association of the receptors with FADD facilitating pro-caspase-8 and/or pro-caspase-10 recruitment which then activates effector caspases to execute cell death [2]. Signalling through DR4 and DR5 can also activate pro-inflammatory intracellular molecules such as MAPK, PKB and NF-κB and overexpression of DR4 or DR5 has been shown to stimulate the release of inflammatory cytokines [3]. However, TRAIL also has three regulatory receptors. Two of these, decoy receptor 1(DcR1) and DcR2 are membrane bound and the third regulatory receptor, osteoprotegerin is a secreted protein. DcRs regulate TRAIL-induced apoptosis by either sequestering TRAIL from the death receptors or by forming inactive, heteromeric DcR1/2–DR4/5 complexes [1]. Indeed, DcRs have been shown to be highly expressed in a number of tumour tissues such as acute myeloid leukaemia, prostate cancer and breast cancer and their expression is linked with poor prognosis [4]. However DcR expression in tumour cells does not correlate with TRAIL sensitivity and non-transformed cells do not require DcRs to be protected from TRAIL-induced apoptosis, suggesting that the in vivo role of the DcRs may be more complex than originally thought [5] \u0000 \u0000The tumor-specific cytotoxicity of TRAIL has been exploited as a therapeutic strategy by utilizing recombinant versions of TRAIL and agonistic antibodies against DR4 and DR5 [6]. While recombinant soluble human TRAIL was highly potent against a broad range of tumours in vitro and in pre-clinical studies, in clinical trials TRAIL has failed to exhibit the same potency [6]. One of the major shortcomings of the preclinical models was the lack of assessment of the contribution of the tumour microenvironment (TME). The TME consists of various cell types, soluble factors and signals from the extracellular matrix, and is in a reciprocal interaction with the tumour cells. It is thus important to understand the interplay of different cell types in the tumour microenvironment and the effect of the factors they express and secrete on tumour growth, development and resistance to therapy. \u0000 \u0000 \u0000 \u0000Figure 1 \u0000 \u0000Cell autonomous and supracellular regulation of TRAIL-sensitivity by decoy receptor 1 (DcR1) and -2 \u0000 \u0000 \u0000 \u0000The study by O'Leary and colleagues explored the hypothesis that DcRs exerted a ‘supracellular level control’ of TRAIL-sensitivity rather than simply regula","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"9 1","pages":"906 - 907"},"PeriodicalIF":0.0,"publicationDate":"2015-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88893847","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 : 2015-11-17DOI: 10.18632/ONCOSCIENCE.266
Jianqiang Wu, Gang Huang, N. Ratner
The Runt-related transcription factor-1 (RUNX1 or AML1) encodes a transcription factor that serves as a master developmental regulator. It is important for hematopoiesis, angiogenesis, maturation of megakaryocytes, and differentiation of T and B cells [1]. Runx1 is also important for neuronal development and glial cell differentiation [2]. Runx1 is integrated into a complex regulatory network which acts both at the transcriptional and post-transcriptional levels. Runx1 activity can be regulated by several posttranslational modifications, including phosphorylation, de-phosphorylation, SUMOylation, acetylation, methylation and ubiquitination. These modifications control various aspects of transcriptional factors' activities such as auto inhibition, dimerization and ubiquitin-mediated degradation [3]. Besides its developmental determination role, RUNX1 is involved in malignant tumor formation. Reports have shown that RUNX1 is frequently de-regulated and has paradoxical effects in human cancers, in which it can function either as a tumor suppressor or oncogene [3, 4]. RUNX1 has been implicated as a tumor suppressor in several solid tumors including breast cancer, esophageal adenocarcinoma, colon cancer and possibly prostate cancer but acts as an oncogene in head/neck squamous cell carcinomas, endometrial cancer, and epithelial cancer [3, 4]. Because Runx1 is a sequence specific DNA-binding transcription factor, whether it functions as oncogene or tumor suppressor is dependent on its interaction with specific co-regulatory proteins. We recently showed that RUNX1 acts as an oncogene in the context of loss of neurofibromatosis type 1 (Nf1). Instead of chromosomal translocation and mutation frequently detected in other cancers, Runx1 is overexpressed in human and mouse neurofibroma-initiating cells, both at the messenger RNA and protein levels. Specifically, loss of Nf1 increases number of embryonic day 12.5 Runx1+/Blbp+ Schwann cell progenitors that enable neurofibroma formation in a mouse model (Figure (Figure1).1). Targeted genetic deletion of RUNX1 in Schwann cells and Schwann cell progenitors delays mouse neurofibroma formation in vivo (5). Figure 1 Model of neurofibromagenesis It is not clear how loss of Nf1 induces Runx1 overexpression and serves as an oncogene. There are several potential possibilities: 1) NF1 is known to encode a Ras-GTPase activating protein (Ras-GAP) and the Ras-MEK-ERK pathway is important for Nf1 neurofibroma formation [6]. Runx1 may be phosphorylated by the elevated MEK signaling to initiate the tumor formation process. 2) Elevated Wnt or Notch signaling can directly or indirectly activate Runx1, which can accelerate G1-S transition and stimulates cell proliferation. Consistently, our results show that loss of Runx1 in Schwann cells decreased cell proliferation by activating Trp53-p21 or increased cell apoptosis by inhibiting anti-apoptotic gene Bcl-2 in the context of Nf1−/− Schwann cell environment
{"title":"Runx1: a new driver in neurofibromagenesis","authors":"Jianqiang Wu, Gang Huang, N. Ratner","doi":"10.18632/ONCOSCIENCE.266","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.266","url":null,"abstract":"The Runt-related transcription factor-1 (RUNX1 or AML1) encodes a transcription factor that serves as a master developmental regulator. It is important for hematopoiesis, angiogenesis, maturation of megakaryocytes, and differentiation of T and B cells [1]. Runx1 is also important for neuronal development and glial cell differentiation [2]. Runx1 is integrated into a complex regulatory network which acts both at the transcriptional and post-transcriptional levels. Runx1 activity can be regulated by several posttranslational modifications, including phosphorylation, de-phosphorylation, SUMOylation, acetylation, methylation and ubiquitination. These modifications control various aspects of transcriptional factors' activities such as auto inhibition, dimerization and ubiquitin-mediated degradation [3]. \u0000 \u0000Besides its developmental determination role, RUNX1 is involved in malignant tumor formation. Reports have shown that RUNX1 is frequently de-regulated and has paradoxical effects in human cancers, in which it can function either as a tumor suppressor or oncogene [3, 4]. RUNX1 has been implicated as a tumor suppressor in several solid tumors including breast cancer, esophageal adenocarcinoma, colon cancer and possibly prostate cancer but acts as an oncogene in head/neck squamous cell carcinomas, endometrial cancer, and epithelial cancer [3, 4]. Because Runx1 is a sequence specific DNA-binding transcription factor, whether it functions as oncogene or tumor suppressor is dependent on its interaction with specific co-regulatory proteins. \u0000 \u0000We recently showed that RUNX1 acts as an oncogene in the context of loss of neurofibromatosis type 1 (Nf1). Instead of chromosomal translocation and mutation frequently detected in other cancers, Runx1 is overexpressed in human and mouse neurofibroma-initiating cells, both at the messenger RNA and protein levels. Specifically, loss of Nf1 increases number of embryonic day 12.5 Runx1+/Blbp+ Schwann cell progenitors that enable neurofibroma formation in a mouse model (Figure (Figure1).1). Targeted genetic deletion of RUNX1 in Schwann cells and Schwann cell progenitors delays mouse neurofibroma formation in vivo (5). \u0000 \u0000 \u0000 \u0000Figure 1 \u0000 \u0000Model of neurofibromagenesis \u0000 \u0000 \u0000 \u0000It is not clear how loss of Nf1 induces Runx1 overexpression and serves as an oncogene. There are several potential possibilities: 1) NF1 is known to encode a Ras-GTPase activating protein (Ras-GAP) and the Ras-MEK-ERK pathway is important for Nf1 neurofibroma formation [6]. Runx1 may be phosphorylated by the elevated MEK signaling to initiate the tumor formation process. 2) Elevated Wnt or Notch signaling can directly or indirectly activate Runx1, which can accelerate G1-S transition and stimulates cell proliferation. Consistently, our results show that loss of Runx1 in Schwann cells decreased cell proliferation by activating Trp53-p21 or increased cell apoptosis by inhibiting anti-apoptotic gene Bcl-2 in the context of Nf1−/− Schwann cell environment","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"379 1","pages":"904 - 905"},"PeriodicalIF":0.0,"publicationDate":"2015-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76614638","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 : 2015-11-16DOI: 10.18632/ONCOSCIENCE.265
D. Del Bufalo, F. Degrassi
The process of cell division represents an extraordinary target to develop antitumor therapies. Indeed, a large number of clinically relevant anti-cancer drugs, such as taxanes and vinca alkaloids, target mitosis by stimulating or inhibiting microtubule (MT) polymerization. During the past decades anti-tubulin drugs have proven very effective against a wide range of tumors. However, collateral effects, such as myelosuppression and MT disruption in non-dividing tissues, including brain, are common. Recently, the increased understanding of the cell division process and the identification of several signaling pathways controlling mitosis have provided novel opportunities for cancer drug discovery. Consequently, mitotic proteins have become attractive targets to develop molecular cancer therapeutics. In this scenario, kinetochores (KTs) represent an attractive therapeutic target in light of their fundamental role in driving chromosome segregation and controlling chromosome segregation errors. Indeed, cells require a fine regulation of the kinetochore-microtubule (KT-MT) attachment stability to prevent chromosome instability, and KT-MT attachment dynamics is often deregulated in tumour cells [2]. Chromosome instability is commonly accepted as a driving force in the development of cancer, but more recent work has demonstrated that extensive chromosome missegregation may be detrimental to cancer cells and act as a tumor suppression mechanism [3]. In light of this double role of chromosome instability in cancer, we have explored the hypothesis that interfering with KT-MT attachment dynamics could drive massive chromosome missegregation and kill tumor cells. Highly Expressed in Cancer protein 1 (Hec1) is a constituent of the evolutionary conserved Ndc80 complex, the molecular connector between KTs and MTs. Among the subunits of the Ndc80 complex, Hec1 directly interacts with MTs and regulates KT-MT dynamics and attachment stability [3]. Importantly, Hec1 is frequently overexpressed in cancer. We previously demonstrated that expression of Hec1 fused with the enhanced green fluorescent protein (EGFP) tag at its N-terminus (EGFP-Hec1), the protein domain that regulates MT attachment dynamics, led to a strong accumulation of this modified protein, which acted as a dominant negative mutant over the endogenous Hec1. Mitotic cells expressing a N-terminus tagged Hec1 accumulated lateral KT-MT attachments and underwent a spindle assembly checkpoint (SAC) dependent mitotic arrest associated with the formation of multipolar spindles [4]. We further showed that expression of an inducible N-terminus modified Hec1 completely abolished in vitro growth of EGFP-Hec1 expressing HeLa cells but had no effects on untransformed human fibroblasts or epithelial cells [5]. These in vitro cell-based data were validated in vivo by showing that inducible EGFP-Hec1 expression strongly inhibited tumor growth in a HeLa xenograft mouse model [5]. Strikingly, in both in vitro and in vivo
细胞分裂过程是开发抗肿瘤疗法的重要靶点。事实上，大量临床相关的抗癌药物，如紫杉烷和长春花生物碱，都是通过刺激或抑制微管(MT)聚合来靶向有丝分裂的。在过去的几十年里，抗微管蛋白药物已被证明对多种肿瘤非常有效。然而，附带效应，如骨髓抑制和MT破坏非分裂组织，包括脑，是常见的。最近，对细胞分裂过程的进一步了解和控制有丝分裂的几个信号通路的鉴定为癌症药物的发现提供了新的机会。因此，有丝分裂蛋白已成为开发分子癌症治疗的有吸引力的靶点。在这种情况下，着丝点(KTs)代表了一个有吸引力的治疗靶点，因为它们在驱动染色体分离和控制染色体分离错误方面起着基本作用。事实上，细胞需要对着丝点-微管(KT-MT)的附着稳定性进行精细调节，以防止染色体不稳定，而在肿瘤细胞中，KT-MT的附着动力学通常是不受调节的[2]。染色体不稳定被普遍认为是癌症发展的驱动力，但最近的研究表明，广泛的染色体错分离可能对癌细胞有害，并起到肿瘤抑制机制的作用[3]。鉴于染色体不稳定性在癌症中的双重作用，我们探索了干扰KT-MT附着动力学可能导致大量染色体错分离并杀死肿瘤细胞的假设。在Cancer protein 1 (Hec1)中高表达，是进化保守的Ndc80复合物的一个组成部分，Ndc80复合物是kt和mt之间的分子连接物，在Ndc80复合物的亚基中，Hec1直接与mt相互作用，调节KT-MT动力学和附着稳定性[3]。重要的是，Hec1在癌症中经常过表达。我们之前已经证明，Hec1在其n端与增强型绿色荧光蛋白(EGFP)标签(EGFP-Hec1)(调节MT附着动力学的蛋白质结构域)融合的表达导致这种修饰蛋白的强烈积累，作为内源性Hec1的显性负突变体。表达n端标记Hec1的有丝分裂细胞积累了侧向KT-MT附着，并经历了与多极纺锤体形成相关的纺锤体组装检查点(SAC)依赖的有丝分裂停滞[4]。我们进一步发现，诱导型n端修饰的Hec1的表达完全抑制了表达HeLa细胞的EGFP-Hec1的体外生长，但对未转化的人成纤维细胞或上皮细胞没有影响[5]。这些基于体外细胞的数据在体内得到验证，表明可诱导的EGFP-Hec1表达强烈抑制HeLa异种移植小鼠模型中的肿瘤生长[5]。引人注目的是，在体外和体内模型中，表达EGFP-Hec1的细胞在有丝分裂中永久停止并产生多极纺锤体。表达EGFP-Hec1的细胞的实时成像显示，多极纺锤体内染色体分离受损诱导有丝分裂灾难，通过诱导有丝分裂引起的凋亡死亡，或细胞分裂失败和多核来鉴定。最后，对MT通量率和KT周转率的测量表明，EGFP-Hec1增加了KT-MT附着的稳定性，这表明稳定KT-MT附着动力学是一种很有前途的治疗方法[5]。与KT-MT附着动力学是抗癌作用的分子靶点一致，在c端表达he1与EGFP融合，不影响KT-MT附着动力学，对癌细胞增殖没有显著影响[5]。总的来说，我们的研究结果表明，多极纺锤体内大量的染色体错分离可以通过激活有丝分裂突变过程来杀死肿瘤细胞。在我们的实验模型中，多极性的诱导是由细胞在前期的时间延长引起的，这促进了内聚疲劳(不协调的着丝粒内聚释放)，并通过泄漏分离酶激活导致中心粒脱离，如图11所示[6,7]。在控制SAC沉默的蛋白质耗尽或抑制后期促进复合物/cdc20 (APC/C)活性后，内聚疲劳依赖性多极性诱导的癌细胞死亡已被证明(图(图1))，其中一些治疗方法被发现在避免有丝分裂滑移和产生癌细胞死亡方面比MT抑制剂更有效(7,8)。这些研究和我们的工作表明，刺激纺锤体多极可以作为一种抗癌策略，通过激活多极有丝分裂后的有丝分裂灾难。 此外，他们指出，靶向参与调节KT-MT附着动力学，纠正KT-MT错误附着或沉默纺锤体组装检查点的机制可能是抗癌策略发展的新前沿。
{"title":"Kinetochore-microtube attachments in cancer therapy","authors":"D. Del Bufalo, F. Degrassi","doi":"10.18632/ONCOSCIENCE.265","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.265","url":null,"abstract":"The process of cell division represents an extraordinary target to develop antitumor therapies. Indeed, a large number of clinically relevant anti-cancer drugs, such as taxanes and vinca alkaloids, target mitosis by stimulating or inhibiting microtubule (MT) polymerization. During the past decades anti-tubulin drugs have proven very effective against a wide range of tumors. However, collateral effects, such as myelosuppression and MT disruption in non-dividing tissues, including brain, are common. Recently, the increased understanding of the cell division process and the identification of several signaling pathways controlling mitosis have provided novel opportunities for cancer drug discovery. Consequently, mitotic proteins have become attractive targets to develop molecular cancer therapeutics. In this scenario, kinetochores (KTs) represent an attractive therapeutic target in light of their fundamental role in driving chromosome segregation and controlling chromosome segregation errors. Indeed, cells require a fine regulation of the kinetochore-microtubule (KT-MT) attachment stability to prevent chromosome instability, and KT-MT attachment dynamics is often deregulated in tumour cells [2]. Chromosome instability is commonly accepted as a driving force in the development of cancer, but more recent work has demonstrated that extensive chromosome missegregation may be detrimental to cancer cells and act as a tumor suppression mechanism [3]. In light of this double role of chromosome instability in cancer, we have explored the hypothesis that interfering with KT-MT attachment dynamics could drive massive chromosome missegregation and kill tumor cells. Highly Expressed in Cancer protein 1 (Hec1) is a constituent of the evolutionary conserved Ndc80 complex, the molecular connector between KTs and MTs. Among the subunits of the Ndc80 complex, Hec1 directly interacts with MTs and regulates KT-MT dynamics and attachment stability [3]. Importantly, Hec1 is frequently overexpressed in cancer. We previously demonstrated that expression of Hec1 fused with the enhanced green fluorescent protein (EGFP) tag at its N-terminus (EGFP-Hec1), the protein domain that regulates MT attachment dynamics, led to a strong accumulation of this modified protein, which acted as a dominant negative mutant over the endogenous Hec1. Mitotic cells expressing a N-terminus tagged Hec1 accumulated lateral KT-MT attachments and underwent a spindle assembly checkpoint (SAC) dependent mitotic arrest associated with the formation of multipolar spindles [4]. We further showed that expression of an inducible N-terminus modified Hec1 completely abolished in vitro growth of EGFP-Hec1 expressing HeLa cells but had no effects on untransformed human fibroblasts or epithelial cells [5]. These in vitro cell-based data were validated in vivo by showing that inducible EGFP-Hec1 expression strongly inhibited tumor growth in a HeLa xenograft mouse model [5]. Strikingly, in both in vitro and in vivo","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"43 1","pages":"902 - 903"},"PeriodicalIF":0.0,"publicationDate":"2015-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82653381","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 : 2015-11-16DOI: 10.18632/ONCOSCIENCE.262
J. Baulida
Mortality in cancer is strongly associated with the capacity of tumor cells to spread and critically affect other tissues and organs. Genetic mutations accumulated by tumor cells and cross-signaling between tumor and host cells underlie the formation of metastasis. Cancer-activated fibroblasts (CAFs), which are host fibroblasts activated by tumor signaling, can alter tumor cell behavior by both paracrine signaling (secreting diffusible molecules) and mechanical signaling (modifying the composition and organization of the stroma). These fibroblasts resemble myofibroblasts (MFs) of the granulation tissue generated during wound healing, which produce a rigid desmoplastic stroma rich in signaling molecules and cross-linked extracellular fibers. Desmoplasia favors malignant tumor cell properties such as mobility, stemness, and even resistance to pharmacological insults [1].
{"title":"Snail1 controls cooperative cell plasticity during metastasis","authors":"J. Baulida","doi":"10.18632/ONCOSCIENCE.262","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.262","url":null,"abstract":"Mortality in cancer is strongly associated with the capacity of tumor cells to spread and critically affect other tissues and organs. Genetic mutations accumulated by tumor cells and cross-signaling between tumor and host cells underlie the formation of metastasis. Cancer-activated fibroblasts (CAFs), which are host fibroblasts activated by tumor signaling, can alter tumor cell behavior by both paracrine signaling (secreting diffusible molecules) and mechanical signaling (modifying the composition and organization of the stroma). These fibroblasts resemble myofibroblasts (MFs) of the granulation tissue generated during wound healing, which produce a rigid desmoplastic stroma rich in signaling molecules and cross-linked extracellular fibers. Desmoplasia favors malignant tumor cell properties such as mobility, stemness, and even resistance to pharmacological insults [1].","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"33 1","pages":"898 - 899"},"PeriodicalIF":0.0,"publicationDate":"2015-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73297482","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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