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Inflammatory Signaling in the Tumor Microenvironment

Institution: 
St. Jude Children's Research Hospital
Researcher(s): 
Peter Murray, PhD
Year Awarded: 
2013
Type of Childhood Cancer: 
Neuroblastoma, Osteosarcoma, Retinoblastoma
Project Description: 

Background
We associate "inflammation" with diseases such as arthritis, inflammatory bowel diseases, bronchitis or rashes. Most of us would not consider cancer an inflammatory disease, yet pathologists first made the link between cancers and inflammatory cells a century ago. Today, there is tremendous interest in cancer and inflammation because of the possibility that inflammation is helping cancer cells survive and proliferate. We study a special cell of the immune system called macrophages. Macrophages get their name from the Greek: "big eater," and are important for many aspects of immunity: macrophages recognize and eat bacteria and viruses as well as dead and dying cells that need to be removed. Macrophages also signal to other cells of the immune system and help organize immune responses. However, macrophages can also become uncontrolled: over-active macrophages can cause excessive inflammation, and become unresponsive to other immune cells that give a "stop" signal to block macrophages' aggressive behavior. Macrophages also invade tumors, often in large numbers.

Project Goals
What are the macrophages doing in tumors: are they helping the cancer cells to grow? Or, do macrophages recognize that the cancer cells are out of control and need to be stopped? The goal of this project is to understand what is special about cancer macrophages. We will focus on cancers of childhood, and use model systems that closely mimic human cancer and translate our findings to human macrophages isolated from childhood cancers.      

UPDATE:  Peter Murray, Ph.D., answered questions about his research (August 2014).

What were you initially studying with your grant funded by ALSF?
The relationship between the immune response and cancer – the basic question was, if the immune response recognizes a tumor is growing in the body, why can’t natural immunity eliminate the malignancy?

What have you found?
We have discovered the underlying mechanism controlling the fate and activity of the main immune cell type inside cancer – macrophages. Macrophages are made in the bone marrow and circulate through the blood to all organs, including tumors. The activity of macrophages in cancer is very controversial. We have taken a big step towards understanding the how and why of macrophage population of tumors.

What does this mean for children with cancer and their families?
Because macrophages are present inside tumors in such high numbers, it is thought they are helping tumors grow. However, deciphering the pro- versus anti-tumor activities has been very complex. We now have a way to rationally ask which is more important – pro- or anti-tumor macrophage functions. The next step is to target the bad response, and enhance the right ones. This can be done with existing drugs, but we have to first have a foundation of basic knowledge.

What are your next steps?
We have to create genetic models of childhood cancer where all the macrophages are "good" or "bad." This is underway, but takes time and a lot of resources to do properly.

Has this research been published?
The first discovery has been submitted for publication.

What has this grant from ALSF allowed you to do that you wouldn’t have been able to do otherwise?
Accelerate the work we were already doing. But slowly. We have been working on this project for ~7 years, and it is painstaking to perform properly. We need support across a long time period because many of our experiments take 1-2 years just to setup.

Why did you choose to work in this field/on this topic?
I am a basic immunologist intrigued by the immune-cancer interface. I’m a curious person who likes to take things apart to see how they work. There are few things in the world as complex as the combination of the immune system and cancer!