Cancer Research

Oncotarget

Oncotarget published "Reversing oncogenic transformation with iron chelation" which reported that cancer cells accumulate iron to supplement their aberrant growth and metabolism.

Depleting cells of iron by iron chelators has been shown to be selectively cytotoxic to cancer cells in vitro and in vivo. A plethora of studies have shown iron chelators can reverse some of the major hallmarks and enabling characteristics of cancer. Iron chelators inhibit signalling pathways that drive proliferation, migration and metastasis as well as return tumour suppressive signalling. Iron chelators target cancer cell metabolism, attenuating oxidative phosphorylation and glycolysis.

Dr. Gina Abdelaal from The Northumbria University said, "Iron is vital for normal cell growth and survival."

Cancer is an evolutionary maverick, which exploits its trademark genomic instability to drain environmental resources. As an enzyme cofactor, iron is responsible for many cellular processes including mitochondrial metabolism and DNA synthesis. As iron can drive cellular proliferation, cancer cells have an adapted iron metabolism allowing increased iron accumulation. The thiosemicarbazone class is a later stage of iron chelator evolution which manifested in 1992.

Unlike their predecessor DFO, thiosemicarbazone chelators are capable of inducing reactive oxygen species. Triapine is a thiosemicarbazone; its primary mode of action is thought to be ribonucleotide reductase inhibition with a higher potency than commonly used ribonucleotide reductase inhibitor, hydroxyurea. This approach is predicted to protect healthy tissues from the cytotoxic effects as the timing and place of the drug release can be controlled.

Encapsulating Dp44mT in PLGA nanoparticles enhanced its ability to induce apoptosis and improved its selectivity towards cancer cells.

At present many more classes of iron chelators are being taken into consideration as potential cancer therapy candidates.

The Abdelaal Research Team concluded in their Oncotarget Research Output that based on the data presented in this review iron chelators could potentially reverse many of the key hallmarks of cancer. Stripping the cells of iron impacts many cellular targets with some targets still undiscovered. NDRG1 has been proven to be the common link between the ability of iron chelators to reverse many of the hallmarks of cancer as overexpression of NDRG1 mimics the impact of iron chelation on several signalling pathways. There are still many unanswered questions about the mechanism of action of iron chelators.

A consensus must be reached on the impact of iron chelation on angiogenesis through in vivo studies. As STAT3 is essential for VEGF gene expression and iron chelation attenuates STAT3 dimerisation and nuclear localisation. The cleaved isoform is only present in cancer cells and could potentially be oncogenic. Although many mechanistic studies have been undertaken iron chelators, the complexity of cell signalling remains a hurdle preventing the discovery of all cellular targets of iron chelation. A potential way of discovering new targets is combining iron chelators with well-characterised cancer therapeutics.

DOI - https://doi.org/10.18632/oncotarget.27866

Full text - https://www.oncotarget.com/article/27866/text/

Correspondence to - Gina Abdelaal - gina.abdelaal@northumbria.ac.uk

Keywords - iron chelator, oncogenesis, selective cytotoxicity, hallmarks of cancer, NDRG1

About Oncotarget

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

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Author Testimonial: Dr. Gina Abdelaal - Northumbria University

Author Insight: Reversing Oncogenic Transformation With Iron Chelation

Oncotarget’s cover paper this week (Volume 12, Issue 24) is entitled, "CCL20 induces colorectal cancer neoplastic epithelial cell proliferation, migration, and further CCL20 production through autocrine HGF-c-Met and MSP-MSPR signaling pathways," by researchers from Research Service, VA Boston Healthcare System, West Roxbury, MA; Harvard Medical School, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Medicine Service, VA Boston Healthcare System, West Roxbury, MA; Brigham and Women’s Hospital, Boston, MA; Surgery Service, VA Boston Healthcare System, West Roxbury, MA.

Abstract:
CCL20-CCR6 interactions promote colorectal cancer through direct effects on neoplastic epithelial cells and through modulating the tumor microenvironment. The mechanism of these effects on neoplastic epithelial cells is poorly understood. This study demonstrates that CCL20 induces secretion of hepatocyte growth factor (HGF) and phosphorylation of HGF’s cognate receptor c-Met in HT29 and HCT116 colorectal cancer cell lines both in concentration- and time-dependent manners. Similar to CCL20, HGF induces migration, autofeedback CCL20 secretion, and ERK1/2 phosphorylation in the colon cancer cells. CCL20-dependent ERK1/2 phosphorylation is blocked by HGF inhibition, and CCL20-dependent migration and CCL20 secretion are blocked by inhibition of HGF or ERK. Interestingly, unlike CCL20, HGF does not induce proliferation of colon cancer cells, and CCL20-dependent cell proliferation is not blocked by direct HGF inhibition. CCL20-dependent proliferation, however, is blocked by the multi-tyrosine kinase inhibitor crizotinib. Exploring this effect, it was found that CCL20 also induces production of MSP and phosphorylation of MSP’s receptor MSPR by the colorectal cancer cells. CCL20-dependent cell proliferation is inhibited by directly blocking MSP-MSPR interactions. Thus, CCL20-mediated migration and CCL20 secretion are regulated through a pathway involving HGF, c-Met, and ERK, while CCL20-mediated proliferation is instead regulated through MSP and its receptor MSPR.

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DOI - https://doi.org/10.18632/oncotarget.28131

Full text - https://www.oncotarget.com/article/28131/text/

Correspondence to - Jason S. Gold - jgold@bwh.harvard.edu

Keywords - CCL20, CCR6, HGF, MSP, colorectal cancer

About Oncotarget

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

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CCL20 and Signaling Pathways in Colorectal Cancer

View the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 24.
https://www.oncotarget.com/archive/v12/i24/

Research Paper (Cover) - “CCL20 induces colorectal cancer neoplastic epithelial cell proliferation, migration, and further CCL20 production through autocrine HGF-c-Met and MSP-MSPR signaling pathways” 
https://doi.org/10.18632/oncotarget.28131

Research Paper - “The potential of PIVKA-II as a treatment response biomarker in hepatocellular carcinoma: a prospective United Kingdom cohort study”
https://doi.org/10.18632/oncotarget.28136

Research Paper - “Caloric restriction causes a distinct reorganization of the lipidome in quiescent and non-quiescent cells of budding yeast”
https://doi.org/10.18632/oncotarget.28133

Research Paper - “Optimization of tumor spheroid model in mesothelioma and lung cancers and anti-cancer drug testing in H2052/484 spheroids”
https://doi.org/10.18632/oncotarget.28134

Research Paper - “Circulating low density neutrophils of breast cancer patients are associated with their worse prognosis due to the impairment of T cell responses”
https://doi.org/10.18632/oncotarget.28135

Research Paper - “Regional and temporal heterogeneity of epithelial ovarian cancer tumor biopsies: implications for therapeutic strategies”
https://doi.org/10.18632/oncotarget.10505

Editorial - “Undetected Barrett’s esophagus: how do we improve early detection?”
https://doi.org/10.18632/oncotarget.28005 (PDF Download)

Research Perspective - “Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma” 
https://doi.org/10.18632/oncotarget.28077 

Keywords - CCL20, colorectal cancer, hepatocellular carcinoma, biomarker, cellular aging, cellular quiescence, cancer patient, lung tumor, breast cancer, ovarian cancer,  Barrett's esophagus, chronic liver disease, cancer, science, research, oncology

About Oncotarget

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

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Table of Contents - Volume 12, Issue 24

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."

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

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

Correspondence to - Electron Kebebew - kebebew@stanford.edu

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

About Oncotarget

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

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Author Testimonial: Dr. Monica Varun Tyagi - Stanford University

Aging (Aging-US)

For Aging’s Volume 11, Issue 18, the Journal devoted the Cover to a research paper by Dr. Alejandro Martin-Montalvo from the Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Sevilla, Spain

Herein, the authors show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan.

Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan.

Dr. Martin-Montalvo said, "The increasing burden of age-related diseases highlights the importance of uncovering the mechanisms underlying the aging process."

TSH stimulates the production of T4 and T3 in the thyroid gland, which in turn inhibit both TRH and TSH synthesis when THs reach the hypothalamus and hypophysis, respectively.

Greater life expectancy has been associated with reduced circulating levels of T4, T3, and/or high TSH levels in both animal models and humans.

In this line, the Laron, Ames and Snell dwarf mice, which have reduced GH signalling and reduced circulating TH levels, exhibit a consistent exceptional lifespan as well as other metabolic alterations such as enhanced hepatic insulin sensitivity.

Both rodents and humans under calorie restriction, which comprises a variety of nutritional interventions with several beneficial effects including extended longevity, exhibit reduced circulating T3 levels and/or high TSH levels.

Likewise, nonagenarians from families with exceptional long lifespans, as well as their descendants, have been reported to exhibit increased TSH levels and/or decreased circulating T3 levels.

The Martin-Montalvo research team concluded, "In 1908 Dr. Max Rubner proposed the rate of living theory of aging and longevity, postulating that species with a low metabolic rate would have increased life expectancy when compared to species with a higher metabolic rate.

In this line, restricted levels of THs, which control the metabolic rate, have been associated with increased longevity as well as metabolic fitness."

Full Text - https://www.aging-us.com/article/102285/text

Correspondence to: Alejandro Martin-Montalvo; email: alejandro.martinmontalvo@cabimer.es and Benoit Raymond Gauthier; email: benoit.gauthier@cabimer.es

Keywords: lifespan, healthspan, thyroid hormones, hyperthyroidism, hypothyroidism, glucose metabolism

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.

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Author Insight: Imbalanced Thyroid Hormones Sensitize to Hepatocarcinogenesis, Unhealthy Aging

Oncotarget published "Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation" which reported that due to the small number of molecular targets in viruses and the rapid evolution of viral genes, it is very challenging to develop specific antiviral drugs.

In addition, HIV-1 and Herpes Simplex virus are known to use IRES as well. By utilizing the crystal structure of the RACK1A protein from the model plant Arabidopsis and using a structure based drug design method, dozens of small compounds were identified that could potentially bind to the experimentally determined functional site of the RACK1A protein.

Dr. Sivanesan Dakshanamurthy from The Georgetown University Medical Center, Dr. Qiyi Tang from The Howard University College of Medicine and Dr. Hemayet Ullah from Howard University said, "With the small number of molecular targets in viruses and the rapid evolution of viral genes, it is very challenging to develop specific antiviral drugs."

Unlike other infectious agents, viruses offer few intrinsic targets for inhibition by antiviral molecules [1]. With their simple structural form and their ability to hijack molecular machinery from host cells to complete their replication cycle, viruses evade most efforts to contain them [2]. However, as viruses require host factors to translate their transcripts, targeting the host factor offers a unique opportunity to develop novel antiviral drugs.

In this regard, identification of the ribosome localized host protein Receptor for Activated C Kinase 1 for viral Internal Ribosomal Entry Site -mediated translation of non-capped mRNAs has been established as a target for developing antiviral drugs [3, 4]. Indeed, many of the animal and human viruses containing IRESs are RNA viruses, and most of them belong only to three families of + ssRNA viruses.

To date, although IRES elements have been widely reported in RNA viruses, only a very limited number of IRES elements have been reported in a few DNA viruses, including Kaposi's sarcoma-associated herpesvirus [7–9], Epstein-Barr virus [10], herpes simplex virus [11], murine gammaherpesvirus 68 [12], Marek's disease virus [13], and simian vacuolating virus 40 [14]. In addition, presence of the IRES in double stranded DNA containing White Spot Syndrome virus, which is in the family Nimaviradae, is also reported [15]. WSSV is widely known as the causative pathogen of a serious disease in shrimp [15].

One of the characteristics of HSV infection is its ability to latently infect neurons so that it can be reactivated, thereby causing recurrent infections [21]. Although the clinical symptoms of HSV-caused diseases can be controlled with antiviral drugs, these drugs are not strong enough to stop subclinical transmission [20, 22].

The Dakshanamurthy/Tang/Ullah Research Team concluded in their Oncotarget Research Output that this work will usher a new avenue to develop effective and durable drugs that can potentially circumvent the selection pressure induced drug-resistance scenarios. Future endeavors to generate next generation drugs targeting the host RACK1 protein with enhanced efficacy will advance this approach to a significantly new level where direct targeting anti-viral drugs are slowly being rendered as non-effective in term of their effective durability

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DOI - https://doi.org/10.18632/oncotarget.26907

Full text - https://www.oncotarget.com/article/26907/text/

Correspondence to - Sivanesan Dakshanamurthy - sd233@georgetown.edu, Qiyi Tang - qiyi.tang@howard.edu, and Hemayet Ullah - hullah@howard.edu

Keywords - host targeted antiviral (HTA), herpes simplex virus (HSV), receptor for activated C kinase 1 (RACK1), RACK1 inhibitor, internal ribosomal entry site (IRES)

About Oncotarget

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

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Author Insight: Functional Inhibitor Compounds Inhibit Herpes Simplex Virus Proliferation

The cover for issue 29 of Oncotarget features Figure 2, "Categorisation of samples analysed," from Laes, et al.

- OncoDNA treatment recommendation followed in 60% of cases
- 93% of treatment decisions were made based on a holistic approach combining next generation sequencing (NGS) and multiple biomarker analysis provided by OncoDNA
- 27% of late-stage patients treated with OncoDNA-recommended therapies had overall survival less than 12 months, compared to a typical average of no more than six months
Gosselies, Belgium - April 17, 2018: OncoDNA ("OncoDNA or "the Company"), the healthcare technology company that collates and translates complex cancer biomarker data to make precision medicine a reality, is pleased to announce the publication of a study in the journal Oncotarget evaluating the utility of OncoDNA's comprehensive biomarker analysis and interpretation services in clinical settings.

The study, published online today and titled "The clinical impact of using complex molecular profiling strategies in routine oncology practice", found that combining advanced, comprehensive testing of cancer biomarkers with OncoDNA's proprietary cancer treatment knowledge database can enable oncologists to make better treatment decisions for their patients. This is because OncoDNA's testing combines immunohistochemistry, next generation sequencing (NGS), and other tests including inherited heart condition testing, DNA methylation, and microsatellite instability (MSI) testing, rather than the industry standard of NGS testing alone.

The study analysed samples from 1,057 late-stage and advanced grade cancer patients from over 30 different countries on four continents between January 2015 and January 2016 for whom at least one standard of care treatment had already failed. Samples were analysed either by the sequencing of a solid biopsy only - with either a hotspot panel or comprehensive panel including more than 400 genes - or the study of biomarkers determined by immunohistochemistry and other biomolecular tests, or a combination of both. In order to assess the utility of tumour profiling in clinical practice, the study also analysed the therapeutic decisions made by oncologists after receiving OncoDNA's tumour analysis and treatment recommendation.

Overall, OncoDNA's treatment recommendation was followed in 60.4% of cases and in 99% of the cases that did not follow the recommendation the cited reason was drug unavailability or cost, not clinical consideration. The vast majority of treatment decisions (93.4%) were made based on OncoDNA's combination of tests rather than NGS alone. This is a substantial increase on NGS testing alone, which will typically yield a treatment recommendation in only 30% of cases. For the cases in which OncoDNA's treatment recommendation was followed, 27% of patients had an overall survival of less than 12 months, a significant improvement for late-stage patients, who normally have a life expectancy of no more than six months.

Jean-Pol Detiffe, Chief Executive Officer of OncoDNA, said: "This dataset demonstrates the utility and power of OncoDNA's proprietary, living database and our holistic approach to genomic and molecular profiling. For oncologists, the study suggests our testing and analysis products could represent the best way to make informed therapeutic decisions in clinical practice. Not only were OncoDNA's recommendations followed in the majority of cases, but the study also suggests that our comprehensive testing and analyses could represent the best approach for obtaining useful molecular insight, while reducing physicians' exposure to irrelevant aberrations. As we continue to expand our business through Europe and beyond, these results will help raise awareness of the benefits of our product offering among oncologists and further the healthcare industry's ability to prescribe precision medicine."

Full text - https://www.oncotarget.com/article/24757/text/

Contact

OncoDNA+32 (0) 71 18 35 00

Jean-Pol Detiffe, CEO 
Jean-Francois Laes, CSO

Consilium Strategic Communications+44 (0)20 3709 5700

Amber Fennell, Sukaina Virji, Nicholas Brown, Hendrik Thys oncodna@consilium-comms.com

About Oncotarget

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

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Author Insight: Unique Biomarker Analysis & Interpretation Platform in Clinical Decision-making

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."

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

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

Correspondence to - Electron Kebebew - kebebew@stanford.edu

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

About Oncotarget

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

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