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Tumour Microenvironment
The ‘low oxygen’ environment of solid tumours is leading to a new class of therapies
Introduction
In seeking new and more effective treatments for cancer, scientists are studying the environment in which tumours grow and survive in the human body. Tumours are tissues with similar needs to our other body tissues. However, there are several key differences between the environment where a tumour is growing and the environment of normal tissue. Researchers have recognized that this environment often functions as a barrier that limits the effectiveness of traditional cancer therapies. More recently, these environmental differences have also been investigated as a potential opportunity or a ‘target’ that a new drug or treatment strategy can exploit.
An issue with many cancer therapies is that even though they are targeting cancer cells, they cannot always make clear distinctions between tumour cells and normal cells, leading to complicating side effects of the therapy. For example, traditional chemotherapy attacks cells that are dividing quickly which tumour cells are. However, so are hair cells and cells in the stomach and mouth.
By targeting aspects that are very specific to tumours or their microenvironment, new therapies offer the possibility of sparing healthy tissue and therefore have fewer negative side effects.
The Princess Margaret, together with its research arm, The Campbell Family Institute for Cancer Research, is a world leader in the study of tumour microenvironments, and is active in translating the understanding of the microenvironment into new therapies which are being tested in our clinics today. This article will provide background on this area of medical research, the people leading the investigation, and their findings.
Tumours are Tissues
Like normal healthy tissue, tumours need an energy supply, and this energy is delivered by the blood system. In fact, tumour cells have enormous metabolic needs to support their rapid proliferation. In other words, in order to grow, tumours need access to the system of arteries, veins and capillaries that make up our blood system to supply them with the nutrients they need.
The process by which new blood vessels form in the body is called angiogenesis, and tumours are known to secrete pro-angiogenic factors that stimulate angiogenesis. Once the tumour has access to the blood supply, it has access to nutrients (like oxygen) that are needed for growth and an energy supply (primarily glucose which is converted to ATP through the process of glycolysis). Tumours have very high demands for energy and are thus known to use up a lot of glucose. This need for glucose is, in fact, often used as a way to detect and ‘image’ tumours.
Tumour Angiogenesis
When we cut or wound ourselves, angiogenesis begins almost immediately in order to supply blood to new tissue that forms in order to heal the wound. This angiogenesis takes place in a very controlled and consistent fashion.
In contrast, when scientists observe how new blood vessels form to supply a tumour, they see significant differences from how blood vessels form to support normal tissue. Blood vessels supplying tumours are abnormal. For example, there are large spaces between vessels, the blood flow pattern is not efficient, and there is a long distance for blood to travel from artery to vein. The vessels are also very leaky leading to higher tumour pressure. Below are images comparing the blood vessels supplying normal tissue vs. vessels supplying tumour tissue.
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Tumour vessels |
Images from Konerding, 2001 and Miller, 2005
There are already drugs in use today which block factors involved in the process of angiogenesis and hence slow down or stop the growth and metastasis of cancer.
Bevacizumab (marketed as Avastin) and Sorafenib (marketed as Nexavar) are two examples of ‘angiogenic inhibitors’ that are attempting to ‘starve’ tumours by cutting off their access to the blood system.
Image from Kabbinavar, 2006, Peer Review Press.
Adapted from Bergers G. Benjamin LE, Nat Rev Cancer 2003.
Hypoxia
As scientists use their tools to focus in on the microenvironment of tumours, one of the most striking differences between tumours and normal tissues is how hypoxic (low oxygen) the environment is. The unregulated angiogenesis that occurs in tumours is believed to be an important factor in the development of hypoxia because the new blood vessels that form from this process are very ineffective at delivering oxygen and other nutrients. The blood vessels are leaky and inefficient.
As the chart below shows, the hypoxic microenvironment of tumours is believed to be linked to aggressive tumour behaviour and failure of cancer treatment in certain patients. Tumour cells that lack oxygen are more resistant to chemotherapy and radiation. The adaptation of tumour cells to hypoxia also changes their behaviour in ways that make the cancer cells more malignant and likely to spread to other tissues (metastasize).
How Tumours Adapt to Hypoxia
Scientists are investigating the mechanisms that tumours use to adapt and survive in hypoxic environments where normal tissue cells would die. Scientists in the labs of the Campbell Family Institute have gained a very good understanding in this area. Identification of these mechanisms, which occur only in the tumour cells in their unusual microenvironment, provides new opportunities for developing a therapy or strategy that will target tumour cells but leave normal tissues alone.
Below are three mechanisms that they hope can be used to target tumours.
The HIF Protein—stimulating energy conservation and new blood vessels
HIF stands for hypoxia inducible factor, and it is a protein found only in hypoxic or oxygen-starved environments. This protein serves two key functions in tumours. First, it enables tumour cells to alter their metabolism so that they can survive and produce energy in the absence of oxygen. Thus, because of HIF, tumour cells that lack oxygen become even more dependent on glucose for their survival. Second, HIF is responsible for generating signals to produce more blood vessels by stimulating release of the growth factor VEGF. New drugs that target HIF or VEGF are currently being studied to see if they can improve cancer control rates either on their own or in combination with radiotherapy or chemotherapy.
Tumours can reduce their requirement for energy
One of the key observations made by scientists studying tumour microenvironments is that this environment is not homogeneous. Rather hypoxic areas are spread throughout the tumour environment, with some of the areas being well-oxygenated and others poorly oxygenated. Further, scientists can see that the cells in the hypoxic areas are able to ‘dial down’ their need for energy in order to adapt and survive in this environment. Understanding just how they are able to do this presents another adaptive mechanism that can be targeted. Drugs that target these adaptive pathways and reduce the ability of cancer cells to survive in the absence of oxygen or glucose may help improve the survival of cancer patients in the future.
Autophagy—a new way for tumour cells to create their own energy
Even when tumour cells cannot obtain the nutrients they need from the blood supply, they have another option. Scientists have observed that tumour cells have the ability to devour parts of themselves in order to survive where there is no other source of energy. This self-cannibalization is important for the tumour cell to meet its energy demand; whereas, it is not generally required in normal tissue cells. Once again, this selective need by the tumour cells presents a potential vulnerability that can be exploited with new therapies aimed at disabling metabolic control in tumours.
Taking this Knowledge to the Clinic: Translational Research
Research hospitals like The Princess Margaret are conducting research in many areas of cancer medicine, and moving the discoveries to the clinic where they can help patients as quickly as possible. The Princess Margaret leads the world in terms of the percentage of patients participating in clinical trials of new treatments.
Currently, the new understanding and theories of hypoxic tumour environments gained in the laboratories are being tested and further studied in the radiation clinics with patients who are being treated for cervix cancer. Ongoing studies have already shown that women with cervix cancer do better if their tumour is in a well-oxygenated, low pressure environment vs. a hypoxic, high pressure environment.
DFS stands for disease free survival
In addition, women receiving radiotherapy for cervix cancer at Princess Margaret Hospital are combining standard treatment with the use of a drug called Sorafenib that blocks angiogenesis. Once the testing is complete, the study/trial will show whether high or low doses of Sorafenib in combination with radiation improves outcomes for these women. On a scheduled basis during treatment, the condition of the women participating in this study is assessed using tumour biopsies and sophisticated imaging techniques with CT and MRI scans. Together, these tests provide valuable information about whether the use of Sorafenib impacts tumour oxygen levels, tumour pressure, and ultimately tumour size and patient survival.
Measuring Tumour Hypoxia and Tumour Metabolism: Tools and Technology
To assess the impact of tumour hypoxia as a contributing factor in the aggressive behaviour of cancer, and then measure the impact of treatment strategies that target tumour hypoxia, state of the art technology to measure tumour hypoxia is required. Often it must be customized for the very specific purposes needed.
Below are descriptions of some of the important tools allowing scientists and doctors to study and measure tumour hypoxia and metabolism.
Tumour Biopsies
The most common way that doctors currently measure tumour hypoxia and metabolism is through the use of biopsies that capture small pieces of tumour tissue. Using various stains and techniques, pathologists can study the tissue and determine the oxygenation level and also the levels of other nutrients like glucose that feed the tumour and allow it to grow. Tumour biopsies allow microscopic evaluation, and can thus assess changes in oxygenation and metabolism at the level of individual tumour cells.
Below is an image of tumour tissue obtained through a biopsy that has been treated with special stains to highlight regions of hypoxia. The red and green areas are hypoxic.
PET (Positron Emission Tomography) Imaging
PET scans are often referred to as ‘metabolic scans’ because they can be used to measure the amount of glucose that the tumour is using, which is an important source of energy for growing cancers. PET scans can also be used to produce images based on other types of biologic properties, including tumour hypoxia and cellular proliferation. This biological imaging tool is complementary to more standard physical imaging tools such as X-rays and CT scans.
Because tumour tissue is usually made up of cells that are growing and proliferating rapidly, it has a high demand for energy and other nutrients. Glucose is an important source of energy and nutrients, and thus tumour tissues absorb and metabolize very large amounts of glucose. Because of this feature, PET scans are ideal for highlighting areas of cancerous tumour growth. PET scans can even distinguish heterogeneities within the microenvironment of tumours, which may indicate zones with different metabolic activity (e.g., hypoxic tumour areas).
Below are examples of PET scans with areas of solid black highlighting areas of high metabolic activity or high levels of glucose activity. Some tissues are consistently areas of high glucose uptake in a healthy or unhealthy body. For example, the heart will always be highlighted because it is taking in large amounts of glucose in order to do its job of pumping blood.
The procedure for a PET scan involves the injection into a vein of a glucose solution that is tagged with a radioactive nuclide. This solution is absorbed by the body over a period of 30 to 60 minutes. After this time, the patient lies down on the platform of the PET scanner and the scanning process begins. A PET scanner resembles a CT scanner—a large donut-shaped machine with a hole through which the body passes.
PET scans are typically taken and used in combination with CT scans. CT scans show anatomically where a tumour is located, while the PET scan shows its level of activity.
PET Scan of the Human Brain
Bioluminescence Imaging
The research team at The Princess Margaret has been refining an established technique called bioluminescence imaging for the purpose of measuring the products of tumour metabolism. As you can see in the images shown below, this technique can highlight areas of high energy (ATP) in a tumour as well as show how much waste product is generated. Lactate is the most common waste product generated by glycolysis (the process that produces glucose).
Biographies of the Research Leaders
Bradly G. Wouters, BEng, PhD
Dr. Wouters is a Senior Scientist at the Campbell Family Institute and Director of the Hypoxia and Microenvironment Program at the Ontario Cancer Institute at Princess Margaret Hospital. He is a Professor in the Departments of Radiation Oncology and Medical Biophysics at the University of Toronto. He is also a Senior Investigator in the Selective Agents Program at the Ontario Institute for Cancer Research (OICR). Dr. Wouters was the recipient of the 2008 Michael Fry Research Award (formerly known as the Radiation Research Award).
His lab is investigating tumour microenvironments with a primary interest in understanding the cellular and molecular responses to deficiencies in oxygenation (hypoxia) and their influence on the biological behaviour of tumours.
Dr. Michael Milosevic MD, FRCPC
Dr. Milosevic is a Professor in the Department of Radiation Oncology at the University of Toronto and a Radiation Oncologist at Princess Margaret Hospital with clinical interests in gynecologic and genitourinary malignancies. His research revolves around new biology-based approaches to improving the effectiveness of radiotherapy for patients with cervix or prostate cancer, particularly in relation to low levels of oxygen in these tumors. Dr. Milosevic’s other main research interest is in the application of image-guided, adaptive, intensity modulated radiotherapy (IMRT) to treat cancer. He is a co-founder of the STTARR Research Program and the STTARR Innovation Centre in Toronto, which integrate molecular, cellular, animal and patient imaging with precision radiation research in a manner conducive to the rapid translation of novel treatment strategies from the laboratory to the clinic.
Glossary
Angiogenesis
the formation and development of blood vessels
ATP
adenosine triphosphate—a key energy-carrying molecule in biological systems. It is produced in the body through the process of cell respiration
Autophagy
the process of self-digestion by a cell through the action of enzymes originating within the same cell—a type of self-cannibalization
Avascular
not associated with or supplied by blood vessels
Bioluminescence
the production of light by living organisms
DFS
disease free survival
Glucose
the most common form of sugar, found extensively in the bodies of living things
Glycolysis
the metabolic breakdown of glucose and other sugars that releases energy in the form of ATP
HIF
hypoxia inducible factor—a protein found only in hypoxic or oxygen-starved environments
Hypoxia
inadequate oxygenation of the blood
Metastasis
the transference of disease-producing organisms or of malignant or cancerous cells to other parts of the body by way of the blood or lymphatic vessels or membranous surfaces
Somatic mutation
a mutation or change in inherited characteristics for a cell in the body, caused by a change in a gene or chromosome
Multimedia
Understanding what feeds a tumuor: “Back to the future”
Dr. Bradly Wouters, Director, Hypoxia and Microenvironment Program, Campbell Family Institute
Presentation given at Princess Margaret Hospital Foundation’s Behind the Scenes, 2009
Dr. Wouters talks about the genes involved in cancer, the differences in metabolism between tumour cells and normal cells, and the ways that tumours deal with hypoxic environments.
What Feeds a Tumour? Targeting the Tumour Blood Supply
Dr. Michael Milosevic, Director of Research, Radiation Medicine Program, Princess Margaret Hospital
Presentation given at Princess Margaret Hospital Foundation’s Behind the Scenes, 2009
Dr. Milosevic talks about several clinical trials he is leading in the Radiation Medicine Program. He explains how these trials are providing insight into the differences of the blood supply for tumours vs. normal tissue and how hypoxic tumour environments affect patient outcomes.
Further Reading
The tumour microenvironment as a target for chemoprevention, by Adriana Albini and Michael B. Sporn, Nature Reviews: Cancer
»View Article
The Role of Hypoxia-Induced Factors in Tumor Progression, by Peter Vaupel, Journal of the National Cancer Institute
»View Article
Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects, by Michael Höckel, Peter Vaupel
»View Article
Meeting Report: Exploiting the Tumor Microenvironment for Therapeutics
Cancer Research, published by the American Association for Cancer Research, Inc.
»View Article
The Tumor Microenvironment, by David Gray
»View Article
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