Tumor Biology and Microenvironment Research
Research in tumor biology and microenvironment seeks to understand the interaction of the cancer cell with its microenvironment and how each remodels the other; tumor heterogeneity; and the acquisition of aggressive properties. Tumor metastasis research focuses on the mechanisms of metastasis and metastatic niches, circulating tumor cells, dormancy, and angiogenesis and vasculogenesis.
Research in this area examines cell-cell and cell-matrix interactions and the roles in tumor biology or metastasis played by growth factors and cytokines, transcription factors, adhesion molecules, cytoskeleton and the nuclear matrix, matrix-degrading enzymes, including epigenetic regulation of the genes and post-translational modification of the proteins.
Studies in this area also include those focused on the pathology and biology of solid tumors and tumor-bearing animals and on the development of technology to facilitate such studies. The role of the microenvironment (stroma) created by inflammation and the inflammatory signaling molecules in tumor formation and progression, the effects of hypoxia on invasion and metastasis, the role of somatic stem cells in determining tumor progression and metastatic behavior, as well as control of stem cell niche by tumor microenvironment, are also critical research areas.
Research in this area is supported and directed by the Tumor Biology and Microenvironment Branch and the Tumor Metastasis Branch.
Cytoskeletal and Structural Nuclear Proteins
Research focuses on:
- Cytoskeletal and structural nuclear proteins, cell adhesion molecules, extracellular matrix integrin interactions, epithelial-stromal interactions during tissue development, morphogenesis, tumor growth, matrix degradation, and invasion and metastasis
- The role of proteases in tumor growth and progression, and in tissue-specific homing of tumor cells to distant organs
- Developing appropriate animal and cellular models of metastases
Endocrinology and Glycobiology
Endocrinology studies focus on growth regulation by steroid hormones, with special emphasis on gene expression and regulation, role of coactivators and corepressors, functional consequences of aberrant steroid receptors, steroid receptor-antagonist interactions, and mechanism of hormone independence.
Studies on glycobiology focus on the role of proteoglycans in metastasis and on tumor glycoproteins and functional consequences of aberrant glycosylation on cell adhesion, tumor progression, and metastasis.
Tumor-Immune Cell Interactions and Metastasis
Recent discoveries include detailed information about the ways in which the tumor and its inflammatory stroma create an immune-suppressed microenvironment. Tumor (and sometimes stromal) cells secrete factors, especially NFkB, that induce leukocyte infiltration and initiate inflammation. Both the tumor cells and the immune cells produce cytokines, which in turn promote an immunosuppressive, pro-tumor, and pro-metastatic microenvironment.
Hypoxia may also be a trigger for this cascade. Profiling of the infiltrating leukocytes reveals that both innate and induced immune cells are involved. For example, the immunosuppression inducers IDO-1 and IDO-2 can be expressed by tumor cells to generate an inflammatory stroma that supports survival, metastasis, and chemoresistance via both local and systemic mechanisms.
Also, breast tumors have been shown to induce IL17-secreting gamma delta T cells, which induce expansion of neutrophils; the neutrophils mediate immune suppression by inhibiting CD8+ T-effector cells, allowing metastasis. Understanding the complex interactions among the tumor, stroma, and immune system, as well as developing a detailed characterization of the tumor-infiltrating immune cell profile, are providing new understanding of how to reverse immune escape by tumors.
Tumor Microenvironment and EMT
Tumor cells and associated stroma (including fibroblasts, adipocytes, endothelial cells, and myeloid and lymphoid immune cells) have been shown to have dynamic and reciprocal interactions, and it is increasingly appreciated that the microenvironment can influence the EMT, a process in which epithelial cells transdifferentiate to a more invasive mesenchymal phenotype. EMT confers mesenchymal and invasive properties to cancer cells as well as the capacity to enter the stem-cell state.
For example, hypoxia and the resulting increase in hypoxia-inducible factor-1 can induce EMT in cancer cells by promoting expression of Twist or by activating urokinase receptor (uPAR) signaling. Virtually all stromal cells have been implicated in the induction of EMT in carcinoma cells via secretion of different molecules, including growth factors, inflammatory cytokines, or proteases.
Carcinoma-associated fibroblasts (CAFs) that frequently enrich the stroma have also been shown to promote tumor progression, likely due to the promotion of EMT by TGF-ß. Endothelial cells induce EMT as well, promoting a shift from E-cadherin to N-cadherin expression and causing increased migratory properties in carcinoma cells and the acquisition of stem-cell-like properties.
In clinical samples, tumor cells near the vasculature have little or no E-cadherin expression, suggesting that cells in these areas undergo EMT. Targeting cells in the microenvironment that induce EMT could be a means to inhibit tumor progression by suppressing tumor migration and invasion.