Dr. Isaiah J. Fidler
The University of Texas MD Anderson Cancer Center
Department of Cancer Biology
The major research interests of my laboratory focus on better understanding of the biology of cancer metastasis and the design of new approaches to the therapy of disseminated cancer. A better understanding of the biology of cancer metastasis allowed us to reach three general conclusions. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. We have reported that biologic heterogeneity is found both within a single metastasis (intralesional heterogeneity) and among different metastases (interlesional heterogeneity). This heterogeneity reflects two major processes: the selective nature of the metastatic process and the rapid evolution and phenotypic diversification of clonal tumor growth (which itself results from the inherent genetic and phenotypic instability of many clonal populations of tumor cells). Second, the process of metastasis is selective for cells that succeed in invasion, embolization, survival in the circulation, arrest in a distant capillary bed, and extravasation into and multiplication within the organ parenchyma. Although some of the steps in this process contain stochastic elements, as a whole, metastasis favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm. Thus, metastases can have a clonal origin, and different metastases can originate from the proliferation of different progenitor cells. Third, and perhaps the most important principle for the design of new cancer therapies, is that metastases can only develop in specific organs. The microenvironments of different organs (the ‘soil’) are biologically unique. Endothelial cells in the vasculature of different organs express different cell-surface receptors and growth factors that influence the phenotype of metastases that develop there. In other words, the outcome of metastasis depends on multiple interactions (“cross-talk”) of metastasizing cells with homeostatic mechanisms, which the tumor cells can usurp. Therapy of metastasis, therefore, can be targeted not only against cancer cells themselves, but also against the homeostatic factors that promote tumor-cell growth, survival, angiogenesis, invasion, and metastasis.
Clinical observations of cancer patients and studies with rodent models of cancer have revealed that certain tumors tend to metastasize to specific organs, independently of vascular anatomy, rate of blood flow, and the number of tumor cells delivered to each organ. An interesting demonstration for organ-specific metastasis comes from our studies demonstrating remarkable differences between two murine melanomas in patterns of brain metastasis: one melanoma produced lesions only in the brain parenchyma, whereas the other produced lesions only in the meninges. The growth at different sites within one organ involved interactions between the metastatic cells and the organ microenvironment, in terms of specific binding to endothelial cells and response to local growth factors.
The organ microenvironment determines the metastatic potential of tumor cells. Hence, in order to produce spontaneous metastasis, data from our laboratory established that tumor cells with metastatic potential must be implanted into orthotopic organs. Although tumor cells produce large lesions in the subcutis, the growth in an ectopic environment generally fails to produce metastases. This is certainly the case for human colon cancer cells implanted into the cecum followed by cecectomy, human renal cancer cells implanted into the kidney, followed by nephrectomy, human pancreatic cancer cells implanted into the pancreas, followed by pancreatectomy, human prostate cancer cells implanted into the prostate, and human lung adenocarcinoma cells implanted into the lung, to name a few.
The organ microenvironment definitely influences changes in gene expression of metastatic cells. We reached this conclusion from microarray analysis on several variants of human pancreatic cancer with different metastatic potential. The variant cells were grown in tissue culture, in the subcutis, pancreas, or liver of nude mice. Highly metastatic cells growing in the pancreas or liver expressed significantly higher levels of 226 gene than did nonmetastatic cells. Growth in the subcutis did not yield similar results, indicating that the gene expression profile of human cancer cells depends on the organ microenvironment.
The survival and growth of all cells in the body are dependent on the adequate supply of oxygen and, hence, on the vasculature. Oxygen can diffuse from capillaries only to a limited distance. Our analysis of clinical specimens of lung cancer brain metastasis demonstrated that all proliferating tumor cells are located at a distance of less than 100 μm from the nearest capillary, whereas apoptotic tumor cells are located at a distance exceeding 150 μm from the nearest blood vessel. We therefore hypothesized that the induction of apoptosis in tumor-associated endothelial cells will trigger a second wave of apoptosis in stromal cells and tumor cells regardless of other biologic properties.
We have reported that cancer cells growing in specific organ microenvironments express and release increased levels of proteins, such as EGF, TGF-α, VEGF (A,B,C), and PDGF, to name a few. These ligands can bind to specific receptors on the tumor cells (autocrine) and tumor-associated organ-specific endothelial cells (paracrine). The activation of these receptors leads to stimulation of cell division and survival. Growth factors and their receptors play a pivotal role in the regulation of cancer progression and neovascularization. Overexpression has been shown to correlate with cancer metastasis, resistance to chemotherapy, and hence, poor prognosis. Inhibiting these signaling pathways represents a good strategy for therapeutic intervention. Studies from our laboratory demonstrated that in tumors expressing a high level of TGF-α, VEGF, or PDGF, tumor-associated endothelial cells express phosphorylated receptors and display expression of several antiapoptotic molecules, thus rendering tumor-associated endothelial cells resistant to anticycling drugs.
We have reported that in multiple orthotopic models such as lung adenocarcinoma, pancreatic cancer, colon cancer, ovarian cancer, and prostate cancer, the neoplasms are heterogeneous for expression of growth factors and their receptors. Hence, treatment of the neoplasms requires the combination of tyrosine-kinase inhibitors and chemotherapy.
The antivascular therapy of neoplasms is most encouraging but demands adherence to three principles. First, targeted therapy requires a target. For example, tumors that do not express PDGF are not likely to contain endothelial cells that express phosphorylated PDGF-R. The administration of imatinib to PDGF-negative tumors is not likely to produce beneficial results. Second, because all tumors are biologically heterogeneous, a combination of several therapeutic agents is required. Third, cancer is a chronic disease, so by the time of diagnosis and certainly by the time of clinical trials, tumors have existed for many months or years. The vasculature of these tumors differs significantly from the vasculature in experimental tumors that progress to a measurable size in days or weeks. A chronic disease must be treated chronically, i.e., managed. Thus, antivascular therapy of tumors may require months of continuous treatment before the induction of necrosis and regression of neoplasms.
Program in Cancer Biology
Office: MDA SRB 1.123b (Unit 854)
D.V.M. - Oklahoma State University - 1963
Ph.D. - University of Pennsylvania - 1970