INFECTION, INFLAMMATION, AND LEPTIN IN CANCER

• Sponsoring Institution: State Agricultural Experiment Station
• Project Status: COMPLETE
• Funding Source: STATE
• Reporting Frequency: Annual
• Accession No.: 1003148
• Project Start Date: Jul 1, 2014
• Project End Date: Dec 31, 2016
• Program Code: [(N/A)]- (N/A)

Recipient Organization
PENNSYLVANIA STATE UNIVERSITY
208 MUELLER LABORATORY
UNIVERSITY PARK,PA 16802

Performing Department
Veterinary & Biomedical Sciences

Non Technical Summary
Each year, more than 1.5 million individuals are newly diagnosed with cancer of various internal organs in the US (http://seer.cancer.gov/report_to_nation/‎). In addition, an even larger number of individuals develop skin cancer http://www.skincancer.org/skin-cancer-information/skin-cancer-facts). In fact, cancer is a leading cause of death in the US with > 500,000 cancer related deaths each year (http://seer.cancer.gov/archive/csr/1975_2010/). In addition to the personal travails from cancer, the overall burden of ill health, morbidity, and work loss due to the disease is estimated to cost the nation more than $100 billion annually. Thus, cancer is an important topic to be investigated.Over the last decade, it has been noted that obesity and chronic infection are risk factors for developing cancer, with chronic inflammation serving as a common denominator for the diverse pathways leading up to malignant conversion and progression. In particular, Leptin (the 16 kD protein product of the obesity gene), is a pro-inflammatory cytokine that is aberrantly expressed in many types of cancer. Since Leptin may be an early target for cancer prevention or therapeutic intervention, natural products and synthetic compounds that down regulate Leptin expression need to be screened and evaluated for potential anti-inflammatory and anti-cancer properties.

Animal Health Component

20%

Research Effort Categories

Basic

80%

Applied

20%

Developmental

0%

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
724	2420	1040	50%
724	4099	1040	50%

Knowledge Area
724 - Healthy Lifestyle;

Subject Of Investigation
4099 - Microorganisms, general/other; 2420 - Noncrop plant research;

Field Of Science
1040 - Molecular biology;

Keywords

leptin

cancer

growth

signaling

infection

Goals / Objectives
The overall objective of this research program is to elucidate the role of Leptin in malignant processes and to screen for dietary agents that reverse the effects of Leptin. In order to achieve the research objectives, initial studies with the following specific aims are proposed:Specific Aims:Identification of infectious conditions that lead to aberrant expression of LeptinElucidation of Leptin mediated alterations to cellular growth and signalingScreening of dietary agents for Leptin regulating potential

Project Methods
The overall objective of this research program is to elucidate the role of Leptin in malignant processes and to screen for dietary agents that reverse the effects of Leptin.. In order to achieve the research objectives, initial studies with the following specific aims are proposed:Identification of infectious conditions that lead to aberrant expression of Leptin. Formaldehyde fixed paraffin embedded tissue samples from patients with chronic inflammatory diseases that increase risk of cancer (e.g. inflammatory bowel disease, ulcerative colitis, Crohns' disease, etc.) will be examined (along with appropriate control samples) for Leptin expression using previously standardized antibodies and immune-histochemical methods.Elucidation of Leptin mediated alterations to cellular growth and signaling. Primary cultures of normal cells (from anatomic sites in which Leptin is found to be upregulated in aim 1 above) as well as corresponding cancer cell lines will be tested for alterations in growth rate, serum/growth factor requirements, anchorage dependence, potential for migration and invasion, levels of telomerase, and activation of JAK2-STAT3, PI3K/AKT, and MAPK/ERK pathways upon in vitro exposure to recombinant Leptin. The methods to be employed for this aim are also standardized.Screening of dietary agents for Leptin regulating potential. Synthetic compounds, dietary agents, and natural plant derivatives will be screened in cell culture systems using semi high-throughput technologies for their ability to control the expression of Leptin.Results of experiments described in the first two aims will help elucidate the role of Leptin in infection and inflammation driven malignant processes while the results of the final aim is designed to identify factors that reduce infection/inflammation driven Leptin expression. Future work will test if the agents thus identified have anti-inflammatory activity or the potential to serve as dietary cancer preventive agents.

Progress 07/01/14 to 12/31/16

Outputs
Target Audience:Basic life sciences and biomedical research communities, and the public. Changes/Problems:No technical problems were encountered, however, unfortunately, as noted above, due to personnel changes and failure to refill positions in a timely manner, we recommend termination of this otherwise promising line of investigations. What opportunities for training and professional development has the project provided?Ms. Naomi Yamada, a junior scientist on the project was trained and is currently enrolled in the bioinformatics and genomics doctoral program at Penn State. How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? A sensitive and specific toolkit was developed to investigate the role, methylation states, and expression levels of LEP, LEPR and LEPROT transcript variants in various human cells and cancer cell lines. The results strongly suggested a major role for LEP mediated signaling in human cancer progression. Furthermore, the methylation state and expression levels of the LEP promoter have utility as sensitive diagnostic markers of cancer progression and provide a compelling opportunity for investigating dietary and nutritional approaches to preventing and treating cancers and understanding the mechanisms of cancer progression. Unfortunately, despite the promise and potential, due to changes in personnel and a failure to refill positions, further progress on this project was unable to be made.

Publications

Progress 07/01/14 to 09/30/14

Outputs
Target Audience: Scientific research community and the public. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Research training and mentorship was provided to Naomi Yamada (MS) who is presently a PhD student in the BG program. How have the results been disseminated to communities of interest? Scientific communications will be made by the PIs and students at local and national meetings. What do you plan to do during the next reporting period to accomplish the goals? Applications for external funding of this research are under preparation.

Impacts
What was accomplished under these goals? Cancer is a leading cause of death in the US and a serious worldwide health concern. Whereas much attention has been focused on environmental carcinogens as well as genetic factors as etiologic agents, more recent findings indicate that obesity is directly related to higher risk of developing cancer. Our research has provided mechanistic insights by showing that the obesity hormone Leptin is up-regulated in multiple types of cancer including sarcomas and the more prevalent carcinomas. Moreover, the hormone can enhance cancer development through rapid phosphorylation and activation of the STAT3, ERK 1/2, and AKT signaling pathways leading to up-regulation of growth factors, proteolytic enzymes, and apoptotic inhibitors that result in increased cell proliferation, invasion, and malignant progression. Moreover, samples have been collected in order to investigate the potential for infectious diseases linked to cancers to up-regulate Leptin levels and methods for the analysis of the same have been standardized. If the link between cancer causing infections and Leptin levels is demonstrated modulation of the same by dietary agents would be useful for cancer prevention and control. Applications for external funding of this research are under preparation.

Publications