The conditions within the tumor microenvironment differ considerably from those in normal tissue. Hypoxia (low oxygen levels), low pH (acidic conditions), and low glucose levels are common. In addition, massive cell death occurs, resulting in the release of proteins and other molecules into the surrounding environment. These factors may help or hurt tumor growth (1) Hypoxia results in the generation of oxygen free radicals which lead to DNA damage (mutation). Mechanisms for repairing this damage are also less efficient under hypoxic conditions. The end result is an increase in the mutation rate and greater variation within the tumor population. Another result is that only those cells with mutations that allow them to survive in harsh conditions will continue to grow and contribute to the tumor (2)
Importantly, the conditions within the tumor microenvironment do not affect cancer cells only. The normal cells surrounding a tumor exhibit altered characteristics compared to corresponding cells in normal tissue. These cells also develop mutations, and the tissue is often disorganized compared to normal tissue (3) These abnormal properties might arise in two ways. The conditions of the tumor microenvironment (hypoxia and low pH) may induce mutations, or soluble products (growth factors, cytokines) released from the tumor may alter the genes expressed by stromal cells (1) Interestingly, mutations have been identified in the stroma of non-cancerous tissue collected from breast cancer patients, suggesting that pre-existing genetic alterations in the stroma may provide the foundation for tumor initiation (2)Experiments have illustrated the importance of the stroma in tumor development.
A Closer Look at Tumor: Stroma Interactions
The influence of the tissues surrounding a tumor has been recognized for many years. In 1976, to examine the effect of the environment on tumor growth, rats were treated with a carcinogen to cause mutations. They were then given a drug to inhibit the growth of normal liver cells and part of the liver was removed to provide a strong growth stimulus. Under these conditions, the only cells able to grow were those with mutations that allowed them to avoid the growth inhibitory effect of the drug (i.e. cancer cells). In rats given the carcinogen but not the growth inhibitor, no tumors developed. This experiment suggested that tumors cannot grow when the surrounding tissue is normal; in other words, growth of a tumor from a single mutated cell can only occur when the stromal environment is altered in such a way to allow unrestrained tumor growth.(4)
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