Oncotarget

The cover for issue 36 of Oncotarget features Figure 7, "Knockdown of APOBEC3B is associated with a lower tumor growth in an adrenocortical carcinoma xenograft mouse model," by Gara, et al. which reported that the role of APOBEC3B in adrenocortical carcinoma and the mechanisms through which its expression is regulated in cancer are not fully understood.

Here, the authors report that APOBEC3B is overexpressed in ACC and it regulates cell proliferation by inducing S phase arrest. They show high APOBEC3B expression is associated with a higher copy number gain/loss at chromosome 4 and 8 and TP53 mutation rate in ACC.

GATA3 was identified as a positive regulator of APOBEC3B expression and directly binds the APOBEC3B promoter region.

Both GATA3 and APOBEC3B expression levels were associated with patient survival.

This Oncotarget study provides novel insights into the function and regulation of APOBEC3B expression in addition to its known mutagenic ability.

Dr. Electron Kebebew from Stanford University said, "Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy."

The distinct pattern of DNA base alterations has been characterized in the cancer genome using high throughput deep sequencing technologies, that reflect the underlying mutational process.

Whole-genome and exome mutation analysis of The Cancer Genome Atlas data on multiple cancers has revealed that this pattern is consistent with the deaminase activity of the AID/APOBEC family of enzymes, therefore, implying its significance as an endogenous mutator and a crucial contributor to somatic mutations and genomic instability.

APOBEC3B is overexpressed in ovarian cancer cell lines and high-grade primary ovarian cancers.

In addition, APOBEC3B expression is positively correlated with the total mutation load, as well as, elevated levels of transversion mutations.

Given there are no well-established exogenous factors associated with ACC, the Oncotarget authors postulated whether APOBEC3B could be an endogenous mechanism of genomic instability/mutations in ACC and investigated its function in vitro and in vivo.

The Kebebew Research Team concluded in their Oncotarget Research Paper, "APOBEC3B overexpressed in ACC, and is associated with DNA damage, S phase arrest, higher copy number alterations and TP53 mutations in ACC. For the first time, we demonstrated that GATA3 directly regulates the expression of APOBEC3B and that both are prognostic markers in ACC."

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DOI - https://doi.org/10.18632/oncotarget.27703

Full text - https://www.oncotarget.com/article/27703/text/

Correspondence to - Electron Kebebew - [email protected]

Keywords - adrenocortical carcinoma, APOBEC3B, GATA3, prognosis, DNA damage

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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The cover for issue 26 of Oncotarget features Figure 8, "Proposed mechanism of action of ONC201," from Greer, et al.

TRAIL, a member of the TNF family of ligands, causes caspase–dependent apoptosis through activation of its receptors, death receptor 4 and DR5.

ONC201 was originally identified as a small molecule that inhibits both Akt and ERK, resulting in dephosphorylation of Foxo3a and thereby induces TRAIL transcription.

Recently, two independent groups, Wafik El Deiry at Fox Chase and Michael Andreeff at MD Anderson,reported that ONC201 induces cell death via cell stress mechanisms, independent of TRAIL transcription. Gene expression profiling analysis revealed that ONC201 induces endoplasmic reticulum (ER) stress or integrated stress response –related genes, such as Activating Transcription Factor 4 (ATF4) and C/EBP–homologous protein (CHOP).

The researchers in Dr. Lipkowitz's group at the Center for Cancer Research in the National Cancer Institute observed that ONC201 kills breast cancer cells via a TRAIL–independent mechanism. Time–lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. They found that ONC201 inhibits mitochondrial respiration and induces mitochondrial structural damage. Moreover, they found ONC201 reduces mitochondrial DNA copy number. Importantly, cells dependent on glycolysis, such as fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mitochondrial DNA were resistant to ONC201. ONC201 induced ATF4 and CHOP in breast cancer cells, and the stress response it was partially dependent on the mitochondrial effects of ONC201.

"Our work identifies a novel mechanism of ONC201 cytotoxicity that is based on the disruption of mitochondrial function, leading to ATP depletion and cell death in cancer cells that are dependent on mitochondrial respiration. Our study also suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201" Dr. Stanley Lipkowitz, Chief, Women's Malignancies Branch, NCI.

Full text – https://www.oncotarget.com/article/24...

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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The cover for issue 31 of Oncotarget features Figure 4, "Concentration dose-response curves of sirolimus effect [55 nM–1 nM] on the number of cells per surviving colony in U2OS cell line after 2 weeks exposure," by Vasuri, et al. which reported that the authors evaluated the long-term effects of sirolimus on three different cell in vitro models, cultured in physiological conditions mimicking sirolimus-eluted stent, in order to clarify the effectiveness of sirolimus in blocking cell proliferation and survival.

Three cell lines were selected and growth in 10 ml of Minimum Essential Medium for 5 weeks with serial dilutions of sirolimus.

The number of colonies and the number of cells per colony were counted.

As a result, the number of WPMY-1 surviving colonies increased in a dose-dependent manner when treated with sirolimus, while the number of U2OS colonies progressively decreased.

In conclusion sirolimus showed the well-known cytostatic effect, but with an effect on clonogenic potential different among the different cell types.

Dr. Gianandrea Pasquinelli from The Bologna University said, "Rapamycin (sirolimus) is a widely used cytostatic drug blocking the cell cycle in the phase G1/S through the inhibition of the mammalian target of Rapamycin (mTOR) pathway, that has found several clinical applications, from immunosuppression in diabetes and organ transplantation to cancer therapy and drug-eluting stents (DES)"

Beside to its cytostatic activity, sirolimus was also discovered to protect normal human oral keratinocytes from apoptosis by activating autophagy, and to act as a basal stem cell keratinocyte-protecting drug in irradiated mice.

The effect of sirolimus on mesenchymal cells is unknown, but it is an important issue, since mesenchymal cells such as myofibroblasts and cells promoting vascular calcification play an important role in atherogenesis and vascular restenosis.

Sirolimus seems to block the proliferation and the migration of vascular smooth muscle cells, but we lack information concerning the effects on other cells composing atherosclerotic plaques.

The aim of the present paper is to evaluate the long-term effects of sirolimus, rather than short-term cell survival, on three different cell in vitro models, cultured in Minimum Essential Medium, which simulates physiological conditions (w/o CO2 and glucose, in order to clarify the effectiveness of sirolimus in blocking cell proliferation and survival.

The Pasquinelli Research Team concluded in their Oncotarget Research Paper that the plaque typology and the different cell composition of the plaque, e. g., the presence of inflammatory cells, angiogenesis, prevalence of fibrosis, presence of osteogenic progenitors, may influence the response to sirolimus.

Moreover, it is known that the clonal capacity varies between cells and we should consider this matter when evaluating the effectiveness of eluted stent.

Finally, additional mechanisms can have a role, such as amitotic cell division.

These mechanisms were also observed in human atherogenesis and could be fundamental to evaluate the in vivo effect of sirolimus too.

Full text - https://www.oncotarget.com/article/27554/text/

Correspondence to - Gianandrea Pasquinelli - [email protected]

Keywords - atherosclerosis, cell proliferation, sirolimus, stents

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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The cover for issue 29 of Oncotarget features Figure 5, "In vivo effects of treatment with L-Grb2 in combination with anti-angiogenic therapy in an ovarian tumor model," by Lara, et al. which reported that adaptor proteins such as growth factor receptor-bound protein-2 play important roles in cancer cell signaling. In the present study, the authors examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression in gynecologic cancer models.

Murine orthotopic models of ovarian and uterine cancer were used to study the biological effects of L-Grb2 on tumor growth.

In vitro experiments were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2. Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight.

Reverse-phase protein array analysis identified significant dysregulation of metabolites in ovarian cancer cells after Grb2 downregulation.

L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer.

Dr. Anil K. Sood and Dr. Cristian Rodriguez-Aguayo from The University of Texas MD Anderson Cancer Center said, "Adaptor proteins are essential for signal propagation after receptor tyrosine kinase (RTK) activation."

Druggable targets have often been proteins with enzymatically active sites to which small molecules could bind.

However, the ability to target previously undruggable targets is evolving. Small-molecule inhibitors rely on intracellular targets or antibodies to inhibit the activity of growth factors, cell surface receptors, and cytokines.

The development of nucleic acid interference-based therapeutics has allowed for regulation of gene expression to inhibit elusive targets.

Nucleic acid-based therapeutics involves a process in which RNA molecules or antisense oligonucleotides inhibit gene expression or translation by neutralizing targeted mRNA molecules.

After crossing the cell membrane, ASOs target mRNA directly through complementary base pair interactions, in the nucleus or cytosol, thus blocking and neutralizing targeted mRNAs.

The Sood/Rodriguez-Aguayo Research Team concluded in their Oncotarget Research Paper, "we report that L-Grb2 has promising antitumor activity in preclinical models of ovarian and uterine carcinoma.

Whereas the evidence of L-Grb2's activity against hematological malignancies is promising, whether it is active in clinical trials against solid tumors has yet to be tested.

Therapies targeting the ErbB2 receptor have had limited success in ovarian cancer, but L-Grb2 may be a better target given its status as an important converging point for cancer cell signaling pathways."

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DOI - https://doi.org/10.18632/oncotarget.27667

Full text - https://www.oncotarget.com/article/27667/text/

Correspondence to - Anil K. Sood - [email protected] and Cristian Rodriguez-Aguayo - [email protected]

Keywords - ovarian cancer, nucleic-acid based therapeutics, therapeutic approaches, uterine cancer

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget - Exploring The Role Of Survivin In Neuroendocrine Neoplasms by Oncotarget Podcast

Oncotarget - The Role Of EGFR Mutations In Predicting Recurrence In Lung Adenocarcinoma by Oncotarget Podcast

Oncotarget - Adoptive Cell Therapy In Combination With Checkpoint Inhibitors by Oncotarget Podcast

Oncotarget - Hyperprogression To Immune Blockade Followed By A Response With Cabozantinib by Oncotarget Podcast

Prof. Malka Cohen-Armon and her team at Tel Aviv University's Sackler Faculty of Medicine choose Oncotarget amongst leading medical journals like The New England Journal of Medicine, Nature or The Lancet to publish groundbreaking cancer research.

Here's more: Developing comprehensive granular multi-modal aging clocks will help get a better understanding of the aging processes, establish causal relationships, and identify preventative and recent reports demonstrate an exclusive eradication of a variety of human cancer cells by the modified phenanthridine PJ34.

The efficient eradication of malignant cells in human pancreas cancer xenografts presents a new model of pancreas cancer treatment.

One of the many promising applications of the deep aging clocks built into the generative adversarial networks is generation of synthetic biological data with age as a generation condition.

Dr. Malka Cohen-Armon from the Sackler Faculty of Medicine & the Sagol School of Neuroscience at Tel-Aviv University in Tel-Aviv, Israel said, "Despite a substantial advance in cancer treatment, pancreatic ductal adenocarcinoma (PDAC) have a limited response to current treatments, and a low 5-years survival rate of about 6%."

Furthermore, the authors identified phenanthrenes acting as PARP1 inhibitors that efficiently eradicate a variety of human cancer cells without impairing benign cells.

However, their PARP1 inhibition per-se does not impair nor eradicate human malignant cells, including pancreas cancer cells, PANC1.

In contrast, at higher concentrations than those causing PARP1 inhibition, PJ34, Tiq-A and Phen eradicate a variety of human cancer cells by mitotic catastrophe cell death.

Here, the efficacy of PJ34 to eradicate human pancreas cancer cells is tested in cell cultures and in xenografts.

In xenografts, eradication of human PANC1 cells deduced from a massive reduction of human proteins in the tumors, was measured 30 days after the treatment with PJ34 has been terminated.

The Cohen-Armon Research Team concluded that PJ34, which is permeable in the cell membrane, accessed and eradicated human PDAC cells in xenografts without impairing normal proliferating cells infiltrated into the tumors.

Full text - https://doi.org/10.18632/oncotarget.27268

Correspondence to - Malka Cohen-Armon - [email protected]

Keywords - PJ34, pancreas cancer, stroma, PANC1 cancer xenografts

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit http://www.oncotarget.com or connect with @Oncotarget

Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

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The cover for issue 58 of Oncotarget features Figure 5, "Representative images of KLK6 and HMGA2 IHC staining in the surgical material of a colon cancer patient," by Chen, et al.

In the CRC patients, KLK6 protein levels were elevated in the non-cancerous distant and adjacent tissues, compared to their paired tumor tissues.

Patients with mutant K-RAS tumors had significantly higher level of KLK6 protein in the luminal surface of non-cancerous distant tissue, compared to the corresponding tissues of the patients with K-RAS wild type tumors.

Dr. Natalia A. Ignatenko from the University of Arizona Cancer Center, Tucson, AZ, USA and the Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA said, "Human KLK6, is a member of the kallikrein-related peptidase family of proteins, originally identified and cloned based on its aberrant expression in human breast and ovarian cancer"

As a proteolytic enzyme, KLK6 can contribute to the invasive phenotype of cancer cells via degradation of extracellular matrix proteins, such as collagen, fibronectin, laminin, fibrinogen and activation of matrix metalloproteinases.

The researchers previously reported that introduction of the mutated K-RAS oncogenic driver gene into Caco-2 colon cell line, which express wild type K-RAS, induced KLK6 expression.

Knocking down endogenously overexpressed KLK6 in highly invasive HCT116 cells, which carries K-RAS mutation, was sufficient to decrease the invasive and metastatic properties of this cell line.

In the present study, the authors investigated the consequences of KLK6 overexpression and its enzymatic activity in colon cancer cells.

They found that KLK6 overexpression in colon cancer cells, regardless of its enzymatic activity, induces the expression of transcription associated protein HMGA2, which has been identified as a driver of the CRC progression and metastasis.

The Ignatenko Research Team concluded, "Moreover, disease recurrence was noted in patients with high KLK6 scores and positive HMGA2 staining. Although more robust analysis of the clinical cases is required, our current observations suggest that KLK6 may contribute to the LIN28B-let7-HMGA2 axis and may serve as an early marker of disease recurrence."

Press Release - http://www.oncotarget.com/news/pr/kallikrein-6-protease-advances-colon-tumorigenesis-via-induction-of-the-high-mobility-group-a2-protein

Keywords - colorectal cancer, kallikrein-related peptidase 6 or KLK6, SMAD2/3, epithelial-mesenchymal transition, HMGA2

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit www.oncotarget.com or connect with @OncotargetJrnl

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