Short Communication Bcl-2 Expression Inhibits Liver Carcinogenesis and Delays the Development of Proliferating Foci

Tumor development is thought to require both increased proliferation and inhibition of apoptosis. However , the relationship between cell replication and cell death in liver tumorigenesis is complex because both proliferation and apoptosis increase during hepatocarcinogenesis. To investigate the effect of the anti-apoptotic gene Bcl-2 in liver carcinogenesis, we established a line of double transgenic mice that express transforming growth factor-␣ (TGF-␣) , a liver mitogen , and Bcl-2. Double transgenic mice , TGF-␣ and Bcl-2 single transgenics , and wild type received an injection of diethylnitrosamine at 15 days of age. This alkylating agent induces liver carcinogenesis and its effect is greatly enhanced by TGF-␣. We report that Bcl-2 expression inhibited diethylnitrosamine-induced liver carcinogenesis and counteracted the enhancing effect of TGF-␣. Bcl-2 delayed the growth of proliferative foci at the early stages of carcinogenesis and inhibited cell proliferation in these foci. The effect of Bcl-2 on liver carcinogenesis is consistent with its reported ability to interfere with cell replication. The data demonstrate that the expression of an antiapoptotic gene during liver carcinogenesis causes a delay rather than an increase in tumorigenesis. The discovery that overexpression of Bcl-2 in follicular lymphomas, caused by a chromosomal translocation, inhibits apoptosis without increasing cell proliferation established a new mode of action for oncogenes

Chronicles of hypoxia: Time-series buoy observations reveal annually recurring seasonal basin-wide hypoxia in Muskegon Lake – A Great Lakes estuary

We chronicled the seasonally recurring hypolimnetic hypoxia in Muskegon Lake – a Great Lakes estuary over 3 years, and examined its causes and consequences. Muskegon Lake is a mesotrophic drowned river mouth that drains Michigan\u27s 2nd largest watershed into Lake Michigan. A buoy observatory tracked ecosystem changes in the Muskegon Lake Area of Concern (AOC), gathering vital time-series data on the lake\u27s water quality from early summer through late fall from 2011 to 2013 (www.gvsu.edu/buoy). Observatory-based measurements of dissolved oxygen (DO) tracked the gradual development, intensification and breakdown of hypoxia (mild hypoxia b4 mg DO/L, and severe hypoxia b2 mg DO/L) below the ~6 m thermocline in the lake, occurring in synchrony with changes in temperature and phytoplankton biomass in the water column during July–October. Time-series data suggest that proximal causes of the observed seasonal hypolimnetic DO dynamics are stratified summer water-column, reduced wind-driven mixing, longer summer residence time, episodic intrusions of cold DO-rich nearshore Lake Michigan water, nutrient run off from watershed, and phytoplankton blooms. Additional basin-wide water-column profiling (2011–2012) and ship-based seasonal surveys (2003–2013) confirmed that bottom water hypoxia is an annually recurring lake-wide condition. Volumetric hypolimnetic oxygen demand was high (0.07–0.15 mg DO/Liter/day) and comparable to other temperate eutrophic lakes. Over 3 years of intense monitoring, ~9–24% of Muskegon Lake\u27s volume experienced hypoxia for ~29–85 days/year – with the potential for hypolimnetic habitat degradation and sediment phosphorus release leading to further eutrophication. Thus, time-series observatories can provide penetrating insights into the inner workings of ecosystems and their external drivers

PTP1B regulates Eph receptor function and trafficking

Changes in protein tyrosine phosphatase 1B expression affect duration and amplitude of EphA3 phosphorylation and cell surface concentration

EphA3 biology and cancer

Eph receptor tyrosine kinases control cell-cell interactions during normal and oncogenic development, and are implicated in a range of processes including angiogenesis, stem cell maintenance and metastasis. They are thus of great interest as targets for cancer therapy. EphA3, originally isolated from leukemic and melanoma cells, is presently one of the most promising therapeutic targets, with multiple tumor-promoting roles in a variety of cancer types. This review focuses on EphA3, its functions in controlling cellular behavior, both in normal and pathological development, and most particularly in cancer

Preferential Antibody and Drug Conjugate Targeting of the ADAM10 Metalloprotease in Tumours

ADAM10 is a transmembrane metalloprotease that sheds a variety of cell surface proteins, including receptors and ligands that regulate a range of developmental processes which re-emerge during tumour development. While ADAM10 is ubiquitously expressed, its activity is normally tightly regulated, but becomes deregulated in tumours. We previously reported the generation of a monoclonal antibody, 8C7, which preferentially recognises an active form of ADAM10 in human and mouse tumours. We now report our investigation of the mechanism of this specificity, and the preferential targeting of 8C7 to human tumour cell xenografts in mice. We also report the development of novel 8C7 antibody–drug conjugates that preferentially kill cells displaying the 8C7 epitope, and that can inhibit tumour growth in mice. This study provides the first demonstration that antibody–drug conjugates targeting an active conformer of ADAM10, a widely expressed transmembrane metalloprotease, enable tumour-selective targeting and inhibition

Inhibition of EphA3 Expression in Tumour Stromal Cells Suppresses Tumour Growth and Progression

Tumour progression relies on interactions with untransformed cells in the tumour microenvironment (TME), including cancer-associated fibroblasts (CAFs), which promote blood supply, tumour progression, and immune evasion. Eph receptor tyrosine kinases are cell guidance receptors that are most active during development but re-emerge in cancer and are recognised drug targets. EphA3 is overexpressed in a wide range of tumour types, and we previously found expression particularly in stromal and vascular tissues of the TME. To investigate its role in the TME, we generated transgenic mice with inducible shRNA-mediated knockdown of EphA3 expression. EphA3 knockdown was confirmed in aortic mesenchymal stem cells (MSCs), which displayed reduced angiogenic capacity. In mice with syngeneic lung tumours, EphA3 knockdown reduced vasculature and CAF/MSC-like cells in tumours, and inhibited tumour growth, which was confirmed also in a melanoma model. Single cell RNA sequencing analysis of multiple human tumour types confirmed EphA3 expression in CAFs, including in breast cancer, where EphA3 was particularly prominent in perivascular- and myofibroblast-like CAFs. Our results thus indicate expression of the cell guidance receptor EphA3 in distinct CAF subpopulations is important in supporting tumour angiogenesis and tumour growth, highlighting its potential as a therapeutic target