Tumor-associated Stromal Cells within the Hypoxic Tumor Microenvironment
The tumor microenvironment is comprised of host stromal cells, soluble growth factors and extracellular matrix that plays a critical role for virtually all tumorigenic processes. Tumor-associated stromal alterations are integral components of the tumor microenvironment that contribute to tumor growth and progression. Among many cellular populations, stromal fibroblasts are prominent cell populations of the tumor microenvironment and have been implicated in the development of various cancers including breast and pancreatic cancers. Unlike stromal cells residing in normal tissue, tumor-associated fibroblasts exhibit distinctive tumor-promoting features: they contribute to tumor cell proliferation, inflammation, angiogenesis, invasion and metastatic dissemination.
Despite recent studies demonstrating that tumor-associated fibroblasts promote the malignant progression and metastasis of various tumors, molecular mechanisms that regulate stromal cell-induced tumor progression in the tumor microenvironment are poorly understood.
In particular, my laboratory is interested in the mechanisms underlying the effects of stromal hypoxic signaling in tumorigenesis, angiogenesis and remodeling of the tumor microenvironment. The remodeling response to hypoxia is controlled primarily by hypoxia-inducible transcription factors (HIFs) 1 and 2, and the negative regulator of HIFs, von Hippel Lindau protein (VHL). We employ transgenic animal models in which the hypoxic response has been genetically ablated via deletion of VHL, HIFs and their target genes in various stromal components including fibroblasts in various tumor models to better understand the relationship of tumor-associated fibroblasts to tumor progression in the context of the hypoxic tumor microenvironment.
H&E staining of PyMT mammary tumor reveals significant stromal components.