Cancer Biology:
Cell Biology and Metastasis
Cancer Genetics
Tumor Immunology

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University of Minnesota Cancer Center

Despite recent advances in the diagnosis and treatment of cancer, tumor cell progression and metastasis constitute a major cause of morbidity and mortality in cancer patients. Understanding the molecular and cellular mechanisms that contribute to tumor formation, progression and metastasis is a major challenge in cancer research. Members of the Cancer Biology Track of MICaB graduate program utilize a multidisciplinary approach to study cancer. Research opportunities in many of the faculty laboratories address the genetics and biology of tumor formation, progression, invasion and metastasis. Faculty laboratories also focus on the development of new cancer therapies; including developing new inhibitors of angiogenesis, improving immune-based therapies, and studying novel compounds that can inhibit the growth and/or survival of malignant tumors.

A major area of research emphasis in the Cancer Biology Track is the relationship between genetic changes and biochemical signaling pathways in the development of cancer. Recent years have witnessed an explosion of information regarding how external signals (e.g., growth factors) bind to cell surface receptors and subsequently transduce biochemical signals that ultimately lead to changes in cell survival, proliferation, differentiation, resistance/sensitivity to apoptosis, migration and invasion. Understanding how genetic changes in cancer alter the balance and flow of information through these signaling pathways is at the foundation of understanding how cancer cells survive and proliferate. A thorough understanding of the differences between altered signaling pathways in cancer cells and the homeostatic signaling pathways in normal cells will lead to the design of new therapeutic strategies for suppressing the tumorigenic and invasive potential of malignant tumors. What follows are examples of research opportunities in these broad areas.

David Largaespada is using mutagenesis strategies to search for new cancer genes in mouse models of human cancer. He and his colleagues have determined that loss of a gene designated neurofibromatosis type 1 (NF1) contributes to the survival and proliferation of myeloid leukemia cells.

Abnormalities in the expression and function of transcription factors are also associated with the origin and progression of tumors. Vivian Bardwell studies transcription factors that are involved in development of human lymphoma. One such transcription factor, designated BCL-6, exhibits deregulated expression in diffuse large cell lymphoma. Her laboratory is interested in how BCL-6 regulates gene expression and how deregulated expression of BCL-6 contributes to the development of lymphoma. Michel Sanders' laboratory is investigating the role of the estrogen-induced ZEB1 transcription factor in breast, ovarian, and prostate cancer. This is part of a larger effort to elucidate estrogen signaling cascades in reproductive tissues.

Carol Lange is studying the "cross-talk" between peptide growth factors and steroid hormone receptors in human breast cancer cells. She is specifically testing the hypothesis that ovarian steroid hormones, such as estrogen/progesterone, and growth factors such as epidermal growth factor (EGF), transduce signals that converge on specific pathways culminating in enhanced survival and growth. Understanding the differences between the cross-talk that occurs in normal breast epithelial cells, and the cross-talk that occurs in breast carcinoma cells will provide insight that could lead to new strategies for treating breast cancer. Ameeta Kelekar's laboratory is interested in the regulation of proteins that are involved in the initiation and amplification of apoptosis or programmed cell death, such as the proteolytic caspases and BH3-only members of the Bcl-2 family. Her group has recently identified a novel mechanism of activation of caspase-9, an initiator caspase in mammalian cells. Khalil Ahmed is studying the role of nuclear kinases, especially a kinase termed CK2, in prostate cancer. He and his colleagues have shown that CK2 is a vital contributing factor to tumor growth and resistance to programmed cell death.

Jim McCarthy's laboratory has a longstanding interest in the role of the extracellular matrix in regulating adhesion, motility and invasion of tumor cells. He and his colleagues have focused on an adhesion molecule designated melanoma chondroitin sulfate proteoglycan (MCSP), which is strongly upregulated early in melanoma progression. They have demonstrated that activated MCSP can activate integrins, which are vital cell surface receptors that promote tumor adhesion and migration within extracellular matrices. Furthermore, MCSP directly transduces unique intracellular signals important for melanoma invasion and metastasis. Finally recent work has focused on the importance of MCSP in regulating the activation of specific transmembrane matrix metalloproteinases important for the invasion of tumors.

In ovarian carcinoma, cancer cells are shed from the surface of the ovary into the peritoneal or ascitic fluid. These cells may then adhere to the mesothelial cells and their associated extracellular matrix (ECM) molecules that line the organs of the peritoneum. Subsequently, the ovarian carcinoma cells may migrate through the lining of mesothelial cells and underlying basement membrane to establish secondary growth sites. This multi-step process of adhesion, migration, and invasion eventually results in the death of the patient. Dr. Amy Skubitz is exploring the role of integrins and CD44 in the interaction between ovarian carcinoma and mesothelial cells, and is also investigating how ovarian carcinoma cells that are shed into the ascitic fluid are kept in a nonadherent and/or noninvasive state.

Several investigators are examining perturbations in signaling pathways present in leukemia. The vast majority of leukemias originate in the bone marrow. Non-blood cells in the bone marrow called stromal cells (fibroblast-like cells) are known to produce growth factors and adhesion molecule receptors that can regulate the development of normal and leukemic blood cells. Tucker LeBien's laboratory is examining the role of bone marrow stromal cells in regulating the fate of B-lineage acute lymphoblastic leukemias (ALL). His laboratory has developed novel B-lineage ALL cell lines from patients with this disease, and he and his colleagues are currently determining the signaling pathways that are activated in leukemic cells following stimulation by bone marrow stromal cell products.

Members of the Cancer Biology Track are also developing novel approaches for treating cancer. Christopher Pennell is studying the potential of heat shock proteins to present tumor-derived peptides for the purpose of activating the anti-tumor T-cell response to breast cancer. Scott McIvor is using recombinant retroviral vectors to introduce drug resistance genes into normal hematopoietic cells; that can be used to protect normal cells against the toxicity associated with chemotherapy. Walter Low is using vaccines and adjuvant-based approaches to enhance anti-tumor responses to treat malignant neural tumors, which to date have remained almost completely refractory to conventional therapies.