Cancer is the second leading cause of death in the US. Except for some germ cell cancers, leukemias and lymphomas, metastatic cancer is generally an incurable disease. Recent work has made great strides in our understanding of the genetic changes that lead to cancer. However, our understanding of the consequences of these oncogenic mutations at the cellular level in tissues in which cancers arise has lagged. This laboratory has begun to apply the principles of stem cell biology to understand the biology of the cancer cells found in solid tumors. Preliminary evidence demonstrates that similar to acute leukemia, solid tumors contain distinct populations of tumorigenic and non-tumorigenic cancer cells. The tumorigenic cancer cells can be prospectively identified based upon marker expression. Self-renewal is critical for both normal stem cells and tumorigenic cancer cells. In a normal tissue, stem cell numbers are under tight genetic regulation resulting in the maintenance of a constant number of stem cells in the organ. By contrast, tumorigenic cancer cells have escaped this homeostatic regulation and the number of cells within a tumor with the ability to self renew is constantly expanding, resulting in the inevitable growth of the tumor. The goal of this grant is to begin to understand the similarities and differences of normal stem cells and tumorigenic cancer cells derived from patients with AML or solid tumors. Specifically we plan: Specific Aim # 1. To determine whether a single tumorigenic cancer cell can generate the heterogeneous populations of tumorigenic and non-tumorigenic cancer cells. Specific Aim # 2. To determine whether the proportion of tumorigenic cancer cells in a tumor changes during tumor growth. Specific Aim # 3. To determine whether the phenotype of the tumorigenic cancer cells changes during passage in the xenograft mouse model. Specific Aim # 4. To identify the genomic makeup of tumorigenic cancer cells from multiple tumors and to determine whether tumorigenic solid tumor cancer cells and tumor-initiating leukemia cells share expression of "stem cell genes" with normal stem cells.