Cell Science

Oncotarget

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

Oncotarget recently published "Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model" which reported that the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer.

CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals.

In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable.

Combination of CRC2631 with checkpoint blockade reduces metastasis burden.

Collectively, these Oncotarget findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies.

Dr. Yves C. Chabu from The University of Missouri said, "Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities."

Several bacterial strains have been developed, including the Salmonella enterica serovar Typhimurium strain VNP20009, one of the most studied tumor-targeting strains.

VNP20009 was first isolated in a genetic screen for hyper invasion mutants using a library of mutant strains derived from ultraviolet and chemical mutagenesis of strain 14028.

CRC2631 was derived from a parent strain that was derived from the prototrophic wild-type Salmonella typhimurium LT2 strain.

This collection consists of mutant strains that arose naturally under nutrient-limiting conditions for over four decades, generating a wealth of genetically diverse and potentially attenuated strains.

Similar to prostate cancers in men, these murine carcinomas disseminate throughout visceral organs, differentiate into neuroendocrine prostate cancer, and ultimately kill the host.

The Chabu Research Team concluded in their Oncotarget Research Paper, "Importantly, CRC2631 reduced metastasis incidence in the setting of checkpoint blockade. This is significant because metastasis is the main cause of cancer-associated deaths and no effective immunotherapy against prostate cancer currently exist."

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DOI - https://doi.org/10.18632/oncotarget.2...

Full text - https://www.oncotarget.com/article/27...

Correspondence to - Yves C. Chabu - chabuc@missouri.edu

Keywords - salmonella, cancer targeting, prostate cancer, immunotherapy, TRAMP

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: Evaluations in TRAMP Prostate Cancer Model

Author Testimonial: Dr. Yves C. Chabu - University of Missouri

Aging (Aging-US)

Aging-US published "Effects of estradiol on biological age measured using the glycan age index" which reported that glycan age is a recently developed biomarker based on glycans attached to immunoglobulin G.

In large population cohorts, glycan age associates well with lifestyle and disease-risk biomarkers, while some studies suggested that glycan changes precede development of several age-associated diseases. In this study the authors evaluated effects of estrogen on the glycan age. After the recovery period glycan age returned to baseline values in both groups.

These results suggest that IgG glycans and consequently also the glycan age are under strong influence of gonadal hormones and that estradiol therapy can prevent the increase of glycan age that occurs in the perimenopausal period.

Dr. Gordan Lauc from The Genos Glycoscience Research Laboratory as well as The University of Zagreb said, "The existence of inter-individual differences in the pace of biological aging is an intriguing concept that tries to explain why some people stay healthy until very late chronological age, while other people age faster and have a shorter life expectancy."

A number of biomarkers aimed at an objective estimation of biological age have been developed in the past several years, one of them being the glycan age, which is based on analyzing glycans attached to immunoglobulin G. A key feature of a good biomarker of biological age is that the difference between chronological and biological age should correlate with known biomarkers of an unhealthy lifestyle and that increased biological age should predict future disease development.

Glycans attached to IgG change significantly with age and have been suggested as a promising biomarker of biological age. Furthermore, since glycosylation affects interactions between IgG and different Fc receptors and other ligands, changes in glycosylation have direct effects on the function of the immune system, with multiple functional implications.

IgG glycans have been shown to be a reliable biomarker of aging that explains up to 64% of variation in chronological age. However, IgG glycans are not only biomarkers but also functional effectors that participate in the process of aging. This prevented the calculation of glycan age from the available data since glycan age is based on IgG glycans. Aiming to evaluate the effects of ovarian sex hormone suppression followed by estradiol supplementation on biological age measured by the glycan age these authors reanalysed samples from the same intervention study using state of the art glycoprofiling technology.

The Lauc Research Team concluded in their Aging-US Research Output that recently a modest improvement in epigenetic age was reported in a small group of individuals undertaking quite radical pharmacological intervention and glycan age was shown to slightly improve by exercise. However, all these changes were modest compared to the effects of the suppression of gonadal hormones, which more than doubled glycan age in some of the participants.

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DOI - https://doi.org/10.18632/aging.104060

Full Text - https://www.aging-us.com/article/104060/text

Correspondence to: Gordan Lauc email: glauc@pharma.hr

Keywords: biological age, glycan age, estrogen, aging biomarkers, glycosylation

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at http://www.Aging-US.com​​ or connect with us on:

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

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Author Insight: Effects of Estradiol on Biological Age Measured Using the Glycan Age Index

Oncotarget published this trending research paper on November 3, 2020, entitled, "Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model" by researchers from the Cancer Research Center, Columbia, MO; Department of Immunobiology, Yale University, New Haven, CT; Department of Radiology and Department of Physics and Astronomy, University of Missouri, Columbia, MO; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO; Department of Psychological Sciences, Institute for Data Science & Informatics, University of Missouri, Columbia, MO; Department of Biology, DeSales University, Center Valley, PA; Division of Biological Sciences, University of Missouri, Columbia, MO.

Abstract:
Conventional cancer chemotherapies are not fully efficacious and do not target tumors, leading to significant treatment-related morbidities. A number of genetically attenuated cancer-targeting bacteria are being developed to safely target tumors in vivo. Here we report the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer. CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals. In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable. Moreover, tumor-targeted CRC2631 generates an anti-tumor immune response. Combination of CRC2631 with checkpoint blockade reduces metastasis burden. Collectively, these findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies.

Press release - https://www.oncotarget.com/news/pr/evaluations-in-the-tramp-prostate-cancer-model/

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DOI - https://doi.org/10.18632/oncotarget.27769

Full text - https://www.oncotarget.com/article/27769/text/

Correspondence to - Yves C. Chabu - chabuc@missouri.edu
Keywords - salmonella, cancer targeting, prostate cancer, immunotherapy, TRAMP

About Oncotarget

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

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Paper Spotlight: Bacterial Therapy Experiments in Prostate Cancer

CD Genomics

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5mC and 5hmC Sequencing Methods

Aging-US published this trending theory article on October 6, 2021, entitled, “Iron: an underrated factor in aging” by Dennis Mangan from MTOR LLC, Bakersfield, CA.

Abstract
Iron is an essential element for virtually all living organisms, but its reactivity also makes it potentially harmful. Iron accumulates with aging, and is associated with many age-related diseases; it also shortens the lifespans of several model organisms. Blocking iron absorption through drugs or natural products extends lifespan. Many life-extending interventions, such as rapamycin, calorie restriction, and old plasma dilution can be explained by the effects they have on iron absorption, excretion, and metabolism. Control of body iron stores so that they remain in a low normal range may be an important, lifespan- and healthspan-extending intervention.

Press Release - https://www.aging-us.com/news_room/iron-an-underrated-factor-in-aging

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DOI - https://doi.org/10.18632/aging.203612

Full Text - https://www.aging-us.com/article/203612/text

Correspondence to: Dennis Mangan email: pdmangan@outlook.com

Keywords: iron, aging, oxidative stress, calorie restriction, plasma dilution

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at http://www.Aging-US.com​​ or connect with us on:

SoundCloud - https://soundcloud.com/aging-us​
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
Instagram - https://www.instagram.com/agingjrnl/
YouTube - https://www.youtube.com/agingus​
LinkedIn - https://www.linkedin.com/company/aging​
Pinterest - https://www.pinterest.com/AgingUS/

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

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Trending With Impact: Iron May Influence Aging

Oncotarget published this trending research paper on December 21, 2018, entitled, "Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer" by researchers from the Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH; Department of Dermatology, University of Michigan, Ann Arbor, MI; Division of Developmental Biology, University of Michigan, Ann Arbor, MI; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH; Department of Surgery, University of Cincinnati Cancer Institute, Cincinnati, OH; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI.

Abstract:
Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation. Mouse organoids were generated from tumors of a triple-transgenic mouse model engineered to express an activated GLI2 allele, GLI2A, in Lgr5-expressing stem cells, (mTGOs) or normal mouse stomachs (mGOs). Bone marrow-derived dendritic cells (DCs) were pulsed with conditioned media collected from normal (mGOCM) or cancer (mTGOCM) organoids. Pulsed DCs and CTLs were then co-cultured with either mGOs or mTGOs in the presence of PD-L1 neutralizing antibody (PD-L1Ab). Human-derived gastric cancer organoids (huTGOs) were used in drug and xenograft assays. Hh/Gli inhibitor, GANT-61 significantly reduced the expression of PD-L1 and tumor cell proliferation both in vivo and in vitro. PD-L1Ab treatment induced tumor cell apoptosis in mTGO/immune cell co-cultures. GANT-61 treatment sensitized huTGOs to standard-of-care chemotherapeutic drugs both in vivo and in vitro. Thus, Hh signaling mediates PD-L1 expression in gastric cancer cells and subsequently promotes tumor proliferation.

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DOI - https://doi.org/10.18632/oncotarget.26473

Full text - https://www.oncotarget.com/article/26473/text/

Correspondence to - Yana Zavros - yana.zavros@uc.edu

Keywords - gastric cancer organoids, PD-1, cytotoxic T lymphocytes, dendritic cells

About Oncotarget

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

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

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

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