Pub Date : 2022-03-23DOI: 10.18632/oncoscience.551
M. Belleri, M. Presta
Sphingolipids, a class of compounds composed by a sphingoid base backbone, represent major components of biological membranes, and play a pivotal role in a variety of subcellular signaling processes. Abnormal sphingolipid metabolism sets the basis for the pathogenesis of variety of genetic diseases known collectively as sphingolipidosis, or sphingolipodystrophy. Among them, globoid cell leukodystrophy (also named Krabbe disease; OMIM #245200), is an autosomal recessive sphingolipidosis characterized by degeneration of oligodendroglia and progressive demyelination due to the genetic deficiency of β-galactosylceramidase (GALC; EC 3.2.1.46) [1], a lysosomal acid hydrolase that catalyzes the removal of β-galactose from β-galactosylceramide (GalCer) and other terminal β-galactose-containing sphingolipids. Based on a long-held and recently confirmed “psychosine hypothesis” [2], Krabbe disease may manifest as a consequence of the accumulation of the neurotoxic GALC substrate β-galactosylsphingosine (psychosine) in the central and peripheral nervous system [3]. Thus, most of the studies concerning the biological role of GALC have been performed on Krabbe patients and Galc-deficient twitcher mice (an authentic animal model of the disease [4]), leading to the envision that the major biological function of GALC may consist in its psychosine “scavenging” activity. However, experimental evidence indicates that GALC may act not only as a psychosine scavenger, but its modulation also exerting a series of psychosineindependent effects [5, 6]. For instance, GALC deficiency affects neovascularization in in vitro and in vivo in the presence of negligible, if any changes in psychosine levels [7, 8]. In addition, knock-down of the human GALC ortholog galcb in zebrafish embryos affects cell survival and neuronal differentiation in the absence of any significant accumulation of this metabolite [9]. In this frame, a recent study has shown that Galc knockdown in murine melanoma B16 cells causes a significant increase of the levels of the oncosuppressive sphingolipid ceramide mirrored by a decrease of sphingomyelins, phosphatidylethanolamines and cholesteryl esters, paralleled by an increased concentration of diacylglycerols [10]. These alterations of the lipidomic profile resulted in the inhibition of the tumorigenic activity of murine melanoma B16 cells. Increased levels of ceramide were observed also in GALC-silenced human melanoma A2058 cells and tumor xenografts, with a consequent decrease of their tumorigenic potential [10]. In keeping with these observations, a progressive increase of GALC expression occurs during tumor progression in human pathological skin specimens ranging from common nevi to stage IV melanoma. Again, the levels of GALC expression were inversely related to the levels of ceramide immunoreactivity in the same tumor samples [5, 10]. Together, these findings indicate that GALC might act as an oncogenic enzyme during melanoma progression by decreasin
{"title":"β-Galactosylceramidase in cancer: more than a psychosine scavenger","authors":"M. Belleri, M. Presta","doi":"10.18632/oncoscience.551","DOIUrl":"https://doi.org/10.18632/oncoscience.551","url":null,"abstract":"Sphingolipids, a class of compounds composed by a sphingoid base backbone, represent major components of biological membranes, and play a pivotal role in a variety of subcellular signaling processes. Abnormal sphingolipid metabolism sets the basis for the pathogenesis of variety of genetic diseases known collectively as sphingolipidosis, or sphingolipodystrophy. Among them, globoid cell leukodystrophy (also named Krabbe disease; OMIM #245200), is an autosomal recessive sphingolipidosis characterized by degeneration of oligodendroglia and progressive demyelination due to the genetic deficiency of β-galactosylceramidase (GALC; EC 3.2.1.46) [1], a lysosomal acid hydrolase that catalyzes the removal of β-galactose from β-galactosylceramide (GalCer) and other terminal β-galactose-containing sphingolipids. Based on a long-held and recently confirmed “psychosine hypothesis” [2], Krabbe disease may manifest as a consequence of the accumulation of the neurotoxic GALC substrate β-galactosylsphingosine (psychosine) in the central and peripheral nervous system [3]. Thus, most of the studies concerning the biological role of GALC have been performed on Krabbe patients and Galc-deficient twitcher mice (an authentic animal model of the disease [4]), leading to the envision that the major biological function of GALC may consist in its psychosine “scavenging” activity. However, experimental evidence indicates that GALC may act not only as a psychosine scavenger, but its modulation also exerting a series of psychosineindependent effects [5, 6]. For instance, GALC deficiency affects neovascularization in in vitro and in vivo in the presence of negligible, if any changes in psychosine levels [7, 8]. In addition, knock-down of the human GALC ortholog galcb in zebrafish embryos affects cell survival and neuronal differentiation in the absence of any significant accumulation of this metabolite [9]. In this frame, a recent study has shown that Galc knockdown in murine melanoma B16 cells causes a significant increase of the levels of the oncosuppressive sphingolipid ceramide mirrored by a decrease of sphingomyelins, phosphatidylethanolamines and cholesteryl esters, paralleled by an increased concentration of diacylglycerols [10]. These alterations of the lipidomic profile resulted in the inhibition of the tumorigenic activity of murine melanoma B16 cells. Increased levels of ceramide were observed also in GALC-silenced human melanoma A2058 cells and tumor xenografts, with a consequent decrease of their tumorigenic potential [10]. In keeping with these observations, a progressive increase of GALC expression occurs during tumor progression in human pathological skin specimens ranging from common nevi to stage IV melanoma. Again, the levels of GALC expression were inversely related to the levels of ceramide immunoreactivity in the same tumor samples [5, 10]. Together, these findings indicate that GALC might act as an oncogenic enzyme during melanoma progression by decreasin","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"4 1","pages":"11 - 12"},"PeriodicalIF":0.0,"publicationDate":"2022-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79502067","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 : 2022-02-24DOI: 10.18632/oncoscience.550
Stefania Tagliari de Oliveira, Monica Pavaneli Bessani, T. B. Scandolara, Janaína Carla da Silva, Aedra Carla Bufalo Kawassaki, Pâmella Aparecida Ferreira Fagotti, Vitor Teixeira Maito, Janoário Athanázio de Souza, D. Rech, C. Panis
Metastasis is the leading cause of cancer death. Considering that lymph nodes are the major pathway for cancer spreading and that the metastatic process is under oxidative stress effects, this study aims to evaluate the differential lipid peroxidation profile in the blood of breast cancer patients regarding their lymph nodal status (LN). A total of 105 women diagnosed with breast cancer were included before chemotherapy started. LN was determined by assessing the histopathological analysis of patients’ biopsies, and groups were categorized according to the presence (LN+, n = 48) or absence (LN−, n = 57) of metastases. Lipid peroxidation profiles (LPO) were determined in blood by high-sensitivity chemiluminescence. After patients’ categorization in groups according to their clinicopathological features, LN− patients aged over 50 years presented significantly lower LPO when compared to those under 50 years. Further, LN− patients carrying HER2 positive tumors presented augmented LPO when compared to patients bearing luminal B or triple-negative tumors. LN+ group also had reduced LPO when presented intratumoral clots. The significant contribution of this study was to show that LPO correlates with specific clinical features of patients with breast cancer according to their LN status and that such profile is significantly affected by the presence of metastases.
转移是癌症死亡的主要原因。考虑到淋巴结是癌症扩散的主要途径，并且转移过程受到氧化应激的影响，本研究旨在评估乳腺癌患者血液中脂质过氧化谱的差异与淋巴结状态(LN)的关系。在化疗开始前，共有105名被诊断患有乳腺癌的女性被纳入研究。LN通过评估患者活检的组织病理学分析来确定，并根据转移存在(LN+， n = 48)或不存在(LN−，n = 57)进行分组。采用高灵敏度化学发光法测定血脂质过氧化谱(LPO)。根据患者的临床病理特征进行分组后，50岁以上LN患者的LPO明显低于50岁以下LN患者。此外，携带HER2阳性肿瘤的LN−患者与携带luminal B或三阴性肿瘤的患者相比，LPO增加。LN+组在出现肿瘤内血块时LPO也降低。本研究的重要贡献在于，根据LN状态，LPO与乳腺癌患者的特定临床特征相关，并且这种特征显著受转移灶的影响。
{"title":"Systemic lipid peroxidation profile from patients with breast cancer changes according to the lymph nodal metastasis status","authors":"Stefania Tagliari de Oliveira, Monica Pavaneli Bessani, T. B. Scandolara, Janaína Carla da Silva, Aedra Carla Bufalo Kawassaki, Pâmella Aparecida Ferreira Fagotti, Vitor Teixeira Maito, Janoário Athanázio de Souza, D. Rech, C. Panis","doi":"10.18632/oncoscience.550","DOIUrl":"https://doi.org/10.18632/oncoscience.550","url":null,"abstract":"Metastasis is the leading cause of cancer death. Considering that lymph nodes are the major pathway for cancer spreading and that the metastatic process is under oxidative stress effects, this study aims to evaluate the differential lipid peroxidation profile in the blood of breast cancer patients regarding their lymph nodal status (LN). A total of 105 women diagnosed with breast cancer were included before chemotherapy started. LN was determined by assessing the histopathological analysis of patients’ biopsies, and groups were categorized according to the presence (LN+, n = 48) or absence (LN−, n = 57) of metastases. Lipid peroxidation profiles (LPO) were determined in blood by high-sensitivity chemiluminescence. After patients’ categorization in groups according to their clinicopathological features, LN− patients aged over 50 years presented significantly lower LPO when compared to those under 50 years. Further, LN− patients carrying HER2 positive tumors presented augmented LPO when compared to patients bearing luminal B or triple-negative tumors. LN+ group also had reduced LPO when presented intratumoral clots. The significant contribution of this study was to show that LPO correlates with specific clinical features of patients with breast cancer according to their LN status and that such profile is significantly affected by the presence of metastases.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"7 1","pages":"1 - 10"},"PeriodicalIF":0.0,"publicationDate":"2022-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87523468","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 : 2019-09-01DOI: 10.18632/oncoscience.492
L. Roncati, B. Palmieri
Metastasis of unknown origin (MUO) means that a cancer is detected when it is already in metastasis, but without any evidence of the primary tumor, even after a full clinico-radiological workup, histological examination, immunohistochemical investigations and tissue-of-origin testing. [1] The occult tumor cannot be identified because it has regressed, due to immune system, or because it is too small for imaging; however, it has been proposed that the undetectable size and the apparent dormant status do not preclude the spreading of cancer stem cells from the original tissue, giving rise to bulky mass at distant sites. [2] About 90% of MUOs are adenocarcinomas, the remaining squamous cell carcinomas, neuroendocrine tumors, composite malignancies and poorly differentiated or anaplastic neoplasms. [3] MUO occurs in about 3 to 5% of all oncological patients and it is burdened by a poor prognosis in 80-85% of the cases, due to its wide dissemination; the survival rates range from 6 to 16 months. These rates are lower in those patients with visceral involvement, ranging from 6 to 9 months. [3] Surely, to know the primary tumor is important because it dictates the best treatment plan and the expected outcome. However, thanks to next generation sequencing (NGS), it is nowadays possible to bypass this dogma and to search for driver mutations in hundreds of cancer-related genes with high sensibility and specificity in a 10-days turnaround time, by exploiting formalin-fixed paraffinembedded metastatic bioptic samples or circulating tumor DNA in the patient’s blood. [4] In addition to reveal the clinically actionable mutations for a personalized therapy, this modern technology provides information about the mutational burden and microsatellite instability (MSI). [4, 5] This last datum is particularly relevant because, on May 2017, the U.S. Food and Drug Administration (FDA) has approved the immunotherapy with pembrolizumab for all unresectable or metastatic, MSI-high (MSI-H) or mismatch repair deficient (dMMR), solid malignancies and, thus, pembrolizumab has become the first tissueagnostic cancer drug. [6] Similarly, on November 2018, the FDA has approved the use of larotrectinib for all adult and pediatric solid tumors characterized by neurotrophic tyrosine receptor kinase (NTRK) gene fusion. [7] The adjective ‘agnostic’ (‘without knowledge’ from Ancient Greek) indicates a new subset of anti-cancer drugs (e.g. Keytruda®, Vitrakvi®) targeted towards the tumor on the basis of specific mutations found inside it, without knowing its tissue/site of origin just as happens in MUO. Therefore, the tissue-agnostic cancer drugs represent current treatment options against NTRK fusion-positive or MSI-H/dMMR MUOs. Other pipelines under development include: entrectinib for the therapy of pediatric and adult patients with recurrent or refractory extracranial solid tumors harboring NTRK, c-Ros oncogene 1 (ROS1) or anaplastic lymphoma kinase (ALK) gene fusions; BLU667 and Lo
{"title":"Tissue-agnostic cancer drugs in the fight against molecular subsets of metastases of unknown origin","authors":"L. Roncati, B. Palmieri","doi":"10.18632/oncoscience.492","DOIUrl":"https://doi.org/10.18632/oncoscience.492","url":null,"abstract":"Metastasis of unknown origin (MUO) means that a cancer is detected when it is already in metastasis, but without any evidence of the primary tumor, even after a full clinico-radiological workup, histological examination, immunohistochemical investigations and tissue-of-origin testing. [1] The occult tumor cannot be identified because it has regressed, due to immune system, or because it is too small for imaging; however, it has been proposed that the undetectable size and the apparent dormant status do not preclude the spreading of cancer stem cells from the original tissue, giving rise to bulky mass at distant sites. [2] About 90% of MUOs are adenocarcinomas, the remaining squamous cell carcinomas, neuroendocrine tumors, composite malignancies and poorly differentiated or anaplastic neoplasms. [3] MUO occurs in about 3 to 5% of all oncological patients and it is burdened by a poor prognosis in 80-85% of the cases, due to its wide dissemination; the survival rates range from 6 to 16 months. These rates are lower in those patients with visceral involvement, ranging from 6 to 9 months. [3] Surely, to know the primary tumor is important because it dictates the best treatment plan and the expected outcome. However, thanks to next generation sequencing (NGS), it is nowadays possible to bypass this dogma and to search for driver mutations in hundreds of cancer-related genes with high sensibility and specificity in a 10-days turnaround time, by exploiting formalin-fixed paraffinembedded metastatic bioptic samples or circulating tumor DNA in the patient’s blood. [4] In addition to reveal the clinically actionable mutations for a personalized therapy, this modern technology provides information about the mutational burden and microsatellite instability (MSI). [4, 5] This last datum is particularly relevant because, on May 2017, the U.S. Food and Drug Administration (FDA) has approved the immunotherapy with pembrolizumab for all unresectable or metastatic, MSI-high (MSI-H) or mismatch repair deficient (dMMR), solid malignancies and, thus, pembrolizumab has become the first tissueagnostic cancer drug. [6] Similarly, on November 2018, the FDA has approved the use of larotrectinib for all adult and pediatric solid tumors characterized by neurotrophic tyrosine receptor kinase (NTRK) gene fusion. [7] The adjective ‘agnostic’ (‘without knowledge’ from Ancient Greek) indicates a new subset of anti-cancer drugs (e.g. Keytruda®, Vitrakvi®) targeted towards the tumor on the basis of specific mutations found inside it, without knowing its tissue/site of origin just as happens in MUO. Therefore, the tissue-agnostic cancer drugs represent current treatment options against NTRK fusion-positive or MSI-H/dMMR MUOs. Other pipelines under development include: entrectinib for the therapy of pediatric and adult patients with recurrent or refractory extracranial solid tumors harboring NTRK, c-Ros oncogene 1 (ROS1) or anaplastic lymphoma kinase (ALK) gene fusions; BLU667 and Lo","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"23 1","pages":"378 - 379"},"PeriodicalIF":0.0,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72970468","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 : 2019-09-01DOI: 10.18632/oncoscience.490
L. Roncati
Worldwide, sick people are daily enjoying the benefits of pet-therapy [1-6]. Next to this scientific evidence, the media report cases of patients who claim to have been saved by their cancer-sniffing pets through an early diagnosis of malignancy. By virtue of this, the concept of ‘canine cancer detection’ has been advanced, on the basis of the presumed olfactory ability of pets, in particular dogs, to smell very low concentrations of aromatic and/or alkanes compounds generated and released by malignant tumors in the patient’s breath, urine or watery stool and into adsorbent materials [7-15]. It is well known that the brain of a domestic dog (Canis lupus familiaris from the Latin) is dominated by a wide olfactory cortex unlike the humans, where a visual cortex predominates. More in detail, dogs are equipped up to 56 times more smellsensitive receptors than the human beings, reaching the number of 280 million in selected breeds, spread over an olfactory surface about the size of a pendrive (9.76 cm2), if compared to 5 million over an area about the size of a postage stamp (3.08 cm2) for the humans [16, 17]. This is thought to render its sense of smell up to 56 times more sensitive than human’s. The domestic cat (Felis silvestris catus from the Latin) also possesses an acute sense of smell, due to its well-developed olfactory bulb and, in addition, to a large surface of olfactory mucosa (about 5.8 cm2), which is almost twice that of the human beings [16]. In oncological medicine, among the diagnostic hallmarks of malignancy there are: lymphovascular and perineural invasion; infiltrative neoplastic growth; immune evasion; a high cytoproliferative index; an elevated mitotic cell count; and tumor necrosis [18, 19]. More in detail, tumor necrosis (νέκρωσις – death from the Greek) is a form of hypoxic death related to the high metabolic demand of cancer cells. It does not follow the apoptotic cascade, but the uncontrolled release of cell death products evokes in the surrounding space an inflammatory response Research Perspective
{"title":"Inside a mystery of oncoscience: The cancer-sniffing pets","authors":"L. Roncati","doi":"10.18632/oncoscience.490","DOIUrl":"https://doi.org/10.18632/oncoscience.490","url":null,"abstract":"Worldwide, sick people are daily enjoying the benefits of pet-therapy [1-6]. Next to this scientific evidence, the media report cases of patients who claim to have been saved by their cancer-sniffing pets through an early diagnosis of malignancy. By virtue of this, the concept of ‘canine cancer detection’ has been advanced, on the basis of the presumed olfactory ability of pets, in particular dogs, to smell very low concentrations of aromatic and/or alkanes compounds generated and released by malignant tumors in the patient’s breath, urine or watery stool and into adsorbent materials [7-15]. It is well known that the brain of a domestic dog (Canis lupus familiaris from the Latin) is dominated by a wide olfactory cortex unlike the humans, where a visual cortex predominates. More in detail, dogs are equipped up to 56 times more smellsensitive receptors than the human beings, reaching the number of 280 million in selected breeds, spread over an olfactory surface about the size of a pendrive (9.76 cm2), if compared to 5 million over an area about the size of a postage stamp (3.08 cm2) for the humans [16, 17]. This is thought to render its sense of smell up to 56 times more sensitive than human’s. The domestic cat (Felis silvestris catus from the Latin) also possesses an acute sense of smell, due to its well-developed olfactory bulb and, in addition, to a large surface of olfactory mucosa (about 5.8 cm2), which is almost twice that of the human beings [16]. In oncological medicine, among the diagnostic hallmarks of malignancy there are: lymphovascular and perineural invasion; infiltrative neoplastic growth; immune evasion; a high cytoproliferative index; an elevated mitotic cell count; and tumor necrosis [18, 19]. More in detail, tumor necrosis (νέκρωσις – death from the Greek) is a form of hypoxic death related to the high metabolic demand of cancer cells. It does not follow the apoptotic cascade, but the uncontrolled release of cell death products evokes in the surrounding space an inflammatory response Research Perspective","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"103 1","pages":"376 - 377"},"PeriodicalIF":0.0,"publicationDate":"2019-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74377279","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 : 2019-08-23DOI: 10.18632/oncoscience.485
Bryson W. Katona, Rebecca A Glynn, Taylor Hojnacki, X. Hua
Menin, the protein product of the MEN1 gene, is a ubiquitously expressed protein that lacks homology with other protein families, yet is highly conserved among various species [1]. Menin primarily resides in the nucleus, where it serves as a scaffold for epigenetic regulators [1, 2]. While much is known about menin and its diverse roles in numerous cellular processes, there remains much to be discovered, especially with regard to its role in cancer.
{"title":"Menin: Expanding and dichotomous roles in cancer","authors":"Bryson W. Katona, Rebecca A Glynn, Taylor Hojnacki, X. Hua","doi":"10.18632/oncoscience.485","DOIUrl":"https://doi.org/10.18632/oncoscience.485","url":null,"abstract":"Menin, the protein product of the MEN1 gene, is a ubiquitously expressed protein that lacks homology with other protein families, yet is highly conserved among various species [1]. Menin primarily resides in the nucleus, where it serves as a scaffold for epigenetic regulators [1, 2]. While much is known about menin and its diverse roles in numerous cellular processes, there remains much to be discovered, especially with regard to its role in cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"44 1","pages":"368 - 370"},"PeriodicalIF":0.0,"publicationDate":"2019-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91522166","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 : 2019-08-23DOI: 10.18632/oncoscience.488
Jianan Zhang, Katherine Z. Sanidad, Guodong Zhang
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Furthermore, it is well established that obese individuals have high risks of developing CRC, and obesity-associated CRC represents an unmet medical problem in the United States. Using a metabolomics approach, our recent research supports that the cytochrome P450 (CYP) monooxygenase/soluble epoxide hydrolase (sEH)-mediated eicosanoid pathway could play critical roles in the pathogenesis of CRC and obesity-associated CRC. Here in this review, we discuss recent studies about the roles of the CYP/sEH eicosanoid pathway in the pathogenesis of these diseases.
{"title":"Cytochrome P450 monooxygenase/soluble epoxide hydrolase-mediated eicosanoid pathway in colorectal cancer and obesity-associated colorectal cancer","authors":"Jianan Zhang, Katherine Z. Sanidad, Guodong Zhang","doi":"10.18632/oncoscience.488","DOIUrl":"https://doi.org/10.18632/oncoscience.488","url":null,"abstract":"Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Furthermore, it is well established that obese individuals have high risks of developing CRC, and obesity-associated CRC represents an unmet medical problem in the United States. Using a metabolomics approach, our recent research supports that the cytochrome P450 (CYP) monooxygenase/soluble epoxide hydrolase (sEH)-mediated eicosanoid pathway could play critical roles in the pathogenesis of CRC and obesity-associated CRC. Here in this review, we discuss recent studies about the roles of the CYP/sEH eicosanoid pathway in the pathogenesis of these diseases.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"137 1","pages":"371 - 375"},"PeriodicalIF":0.0,"publicationDate":"2019-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75761972","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 : 2019-07-01DOI: 10.18632/oncoscience.489
G. Seigel, D. Shah, Pia Mendoza, E. Szalai, H. Grossniklaus, Yinghui Song, J. Shan
Retinoblastoma (RB) is an ocular tumor of early childhood. Current treatments attempt to preserve visual function, but may spare chemoresistant tumor cells. One potential therapeutic target for RB is HER2, (ERBB2), expressed in RB in truncated form. In this study, we tested the hypothesis that Her2 DNA and RNA are expressed in RB tumors and adjacent retina. We examined 24 human RB tumors as well as normal-appearing adjacent retinal tissues for Her2 DNA and RNA expression by in situ hybridization. We also examined 28 RB tumors for HER2 protein immunoreactivity. 21/22 RB tumors expressed Her2 DNA and 14/19 tumors expressed Her2 RNA. In 17 paired cases, there were three cases in which Her2 DNA was detected, but not RNA. We also saw Her2 RNA signal in six instances of “normal” adjacent retinal tissue. Heterogeneous HER2 protein expression in specific tumor regions also was confirmed by quantitative HER2 immunohistochemistry. In summary, Her2 DNA and RNA are expressed in many RB tumors, and in some adjacent ocular tissues, with hetereogenous protein expression throughout. These results may provide important insights regarding RB tumor progression, and drug targeting approaches designed to spare the eye, preserve vision and improve quality of life for RB patients.
{"title":"In situ analysis of Her2 DNA and RNA in retinoblastoma and adjacent retina","authors":"G. Seigel, D. Shah, Pia Mendoza, E. Szalai, H. Grossniklaus, Yinghui Song, J. Shan","doi":"10.18632/oncoscience.489","DOIUrl":"https://doi.org/10.18632/oncoscience.489","url":null,"abstract":"Retinoblastoma (RB) is an ocular tumor of early childhood. Current treatments attempt to preserve visual function, but may spare chemoresistant tumor cells. One potential therapeutic target for RB is HER2, (ERBB2), expressed in RB in truncated form. In this study, we tested the hypothesis that Her2 DNA and RNA are expressed in RB tumors and adjacent retina. We examined 24 human RB tumors as well as normal-appearing adjacent retinal tissues for Her2 DNA and RNA expression by in situ hybridization. We also examined 28 RB tumors for HER2 protein immunoreactivity. 21/22 RB tumors expressed Her2 DNA and 14/19 tumors expressed Her2 RNA. In 17 paired cases, there were three cases in which Her2 DNA was detected, but not RNA. We also saw Her2 RNA signal in six instances of “normal” adjacent retinal tissue. Heterogeneous HER2 protein expression in specific tumor regions also was confirmed by quantitative HER2 immunohistochemistry. In summary, Her2 DNA and RNA are expressed in many RB tumors, and in some adjacent ocular tissues, with hetereogenous protein expression throughout. These results may provide important insights regarding RB tumor progression, and drug targeting approaches designed to spare the eye, preserve vision and improve quality of life for RB patients.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"76 1","pages":"357 - 366"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85516105","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 : 2019-07-01DOI: 10.18632/oncoscience.487
Hui Li, C. Brakebusch
{"title":"Senescence regulation by nuclear N-WASP: a role in cancer?","authors":"Hui Li, C. Brakebusch","doi":"10.18632/oncoscience.487","DOIUrl":"https://doi.org/10.18632/oncoscience.487","url":null,"abstract":"","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"354 - 356"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79824656","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 : 2019-07-01DOI: 10.18632/oncoscience.491
Dana C. Galvan, A. Ayyappan, B. Bryan
[This corrects the article DOI: 10.18632/oncoscience.472.].
[这更正了文章DOI: 10.18632/ onscience .472]。
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Pub Date : 2019-07-01DOI: 10.18632/oncoscience.486
P. Storz
In pancreatic cancer, standard chemotherapy alone or its combination of with checkpoint inhibitors is largely ineffective, because the tumor microenvironment generates a fibrotic barrier for immunotherapy and for drugs to reach tumor cells. Current most promising efforts are strategies that combine chemotherapy with compounds that alter the tumor microenvironment. Here we discuss treatment with pomalidomide as a method to target immunosuppressive alternatively-activated tumor-associated macrophages, resulting in a decrease in fibrosis and formation of an immune-responsive environment. The pancreatic tumor microenvironment (TME) is an immunosuppressive, fibrotic barrier. It blocks the delivery of drugs that target tumor cells, but also excludes immune cells and prevents immunotherapy [1]. Major cell types in the TME are different populations of activated fibroblasts, and immune cells, including tumor-associated macrophages (TAMs). Alternatively-activated (M2) macrophages represent approximately 85% of TAMs in the pancreatic tumor microenvironment [2]. In pancreatic ductal adenocarcinoma (PDA) these macrophages regulate two hallmarks of immune escape, the exclusion of cytotoxic T lymphocytes and fibrosis [3, 4]. Both, either targeting immunosuppressive alternativelyactivated TAMs, or their repolarization to inflammatory macrophages, which drive destruction of the tumor stroma and presence of cytotoxic T cells, could be efficient strategies for this cancer [3-5]. Indeed, preclinical data indicate that neutralization of IL-13, a factor that mediates M2 polarization of macrophages, decreases the presence of alternativelyactivated macrophages, as well as fibrosis at pancreatic lesions [4]. In recent work, Bastea et al. now show that pomalidomide, a thalidomide analog that has been developed and tested for hematologic cancers [6], not only induces a decrease in alternatively-activated macrophages, which then results in decreased fibrosis at PanIN lesions and tumors, it also reprograms these populations into tumor suppressive macrophages [7]. Effects of pomalidomide on M2 macrophages are due to downregulation of interferon regulatory factor 4 (IRF4), a transcription factor for M2 macrophage polarization. Through its effects on macrophage populations pomalidomide generates a pro-inflammatory environment by decreasing tissue levels of interleukin 1 receptor antagonist (IL-1ra) and increasing Interleukin 1α (IL-1α), with the net effect of activating interleukin 1 receptor (IL-1R) signaling [7]. It had been shown previously that pancreatic tumors deficient of IL-1α have an immunosuppressive environment due to exclusion of cytotoxic T cells [8]. As expected, due to re-establishing IL-1R signaling, pomalidomide induced presence of activated (IFNγ-positive) CD4+ and CD8+ T cell populations [7]. This is in line with studies showing that in the pancreas shifting M2 to M1 populations orchestrates effective T cell immunotherapy [9]. In addition to its effects on im
{"title":"Pomalidomide-induced changes in the pancreatic tumor microenvironment and potential for therapy","authors":"P. Storz","doi":"10.18632/oncoscience.486","DOIUrl":"https://doi.org/10.18632/oncoscience.486","url":null,"abstract":"In pancreatic cancer, standard chemotherapy alone or its combination of with checkpoint inhibitors is largely ineffective, because the tumor microenvironment generates a fibrotic barrier for immunotherapy and for drugs to reach tumor cells. Current most promising efforts are strategies that combine chemotherapy with compounds that alter the tumor microenvironment. Here we discuss treatment with pomalidomide as a method to target immunosuppressive alternatively-activated tumor-associated macrophages, resulting in a decrease in fibrosis and formation of an immune-responsive environment. The pancreatic tumor microenvironment (TME) is an immunosuppressive, fibrotic barrier. It blocks the delivery of drugs that target tumor cells, but also excludes immune cells and prevents immunotherapy [1]. Major cell types in the TME are different populations of activated fibroblasts, and immune cells, including tumor-associated macrophages (TAMs). Alternatively-activated (M2) macrophages represent approximately 85% of TAMs in the pancreatic tumor microenvironment [2]. In pancreatic ductal adenocarcinoma (PDA) these macrophages regulate two hallmarks of immune escape, the exclusion of cytotoxic T lymphocytes and fibrosis [3, 4]. Both, either targeting immunosuppressive alternativelyactivated TAMs, or their repolarization to inflammatory macrophages, which drive destruction of the tumor stroma and presence of cytotoxic T cells, could be efficient strategies for this cancer [3-5]. Indeed, preclinical data indicate that neutralization of IL-13, a factor that mediates M2 polarization of macrophages, decreases the presence of alternativelyactivated macrophages, as well as fibrosis at pancreatic lesions [4]. In recent work, Bastea et al. now show that pomalidomide, a thalidomide analog that has been developed and tested for hematologic cancers [6], not only induces a decrease in alternatively-activated macrophages, which then results in decreased fibrosis at PanIN lesions and tumors, it also reprograms these populations into tumor suppressive macrophages [7]. Effects of pomalidomide on M2 macrophages are due to downregulation of interferon regulatory factor 4 (IRF4), a transcription factor for M2 macrophage polarization. Through its effects on macrophage populations pomalidomide generates a pro-inflammatory environment by decreasing tissue levels of interleukin 1 receptor antagonist (IL-1ra) and increasing Interleukin 1α (IL-1α), with the net effect of activating interleukin 1 receptor (IL-1R) signaling [7]. It had been shown previously that pancreatic tumors deficient of IL-1α have an immunosuppressive environment due to exclusion of cytotoxic T cells [8]. As expected, due to re-establishing IL-1R signaling, pomalidomide induced presence of activated (IFNγ-positive) CD4+ and CD8+ T cell populations [7]. This is in line with studies showing that in the pancreas shifting M2 to M1 populations orchestrates effective T cell immunotherapy [9]. In addition to its effects on im","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"52 1","pages":"351 - 353"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72573522","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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