Role of inflammation in lung carcinoma neovascularization
Initial Award Abstract
Lung cancer, which is predominantly caused by tobacco use, is the leading cause of cancer death and one of the leading causes of death overall in the United States. In fact, more then 87% of lung cancers occur in present or former tobacco users. Currently, few effective treatments exist for lung cancer and most lung cancer patients die within nine to twelve month of diagnosis. Thus, there remains a pressing need for innovative and effective new therapeutics approaches for the treatment of lung cancer.
Recent research has shown that all tumors such as lung, breast, prostate and colon tumors induce the growth of new blood vessels. The growth of blood vessels, called angiogenesis is essential for the growth of the tumor as tumor cells depend strictly on the continuous supply of nutrition and oxygen by the blood. In addition, tumor angiogenesis also enable tumor cells escape and spread to other parts of the body by a process known as metastasis, where they may damage vital organs and cause death.
My studies and those of others indicate that white blood cells form the immune system of the patient carrying a tumor, invade tumors and promote tumor angiogenesis as well as tumor growth. Lung carcinomas are heavily infiltrated by host white blood cells such as monocytes, which can differentiate into tumor-associated macrophages (TAM). TAM’s can release a number of potent factors, which stimulate tumor angiogenesis. Additionally, these macrophages also express a broad array of enzymes which support angiogenesis by remodeling and breaking down the matrix surrounding cells. Thus, the trafficking of monocytes to the tumor environment may contribute significantly to tumor progression. In lung carcinomas, intensive infiltration of monocytes correlates with clinical aggressiveness, high tumor grade, and poor prognosis.
Little is known about how these monocytes enter into lung tumors and cause new blood vessels to grow. Our lab recently showed that the cell adhesion molecule integrin a4b1 (VLA-4) promotes the invasion of tumors by monocytes and that these cells subsequently promote tumor angiogenesis. Under normal circumstances, integrin a4b1 on circulating monocytes is maintained in an inactive form. However, my preliminary studies indicate that lewis lung tumors secret factors which can activate this integrin and thereby promote monocyte invasion. I further analyzed the expression of tumor released factors in lewis lung carcinoma by quantitative real time PCR and revealed a strong upregulation of integrin activating factors in lung tumors compared to normal lung tissue. I showed that the identified factors were able to activate integrin a4b1 resulting in increased binding of these cells to the tumor. These findings suggest that lung tumors directly regulate the binding of monocytes by specifically activating integrins on circulating cells. As the host environment plays dramatic roles in tumor growth and metastasis, it will be important to determine the mechanisms by which tumor released factors and integrin a4b1 cooperate to promote the trafficking of myeloid cells to lung carcinomas.
This work is a novel approach toward developing new therapies for lung tumors. Although much as been learned about new blood vessel formation during tumor growth, only recently have researchers realized the important role of white blood cells (inflammation) in this process. Few studies have been dedicated to learning how monocytes invade the lung tumor environment. These studies could easily lead to the development of novel therapies for the treatment of lung cancer. |