Angiogenesis is a crucial aspect of tumor progression and metastases. Angiogenesis and extracellular matrix (ECM) proteins are highly expressed in many cancers and serum levels of these markers are elevated in thyroid cancer patients. Anti-angiogenic strategies have been highly successful in preclinical models of thyroid cancer including the most aggressive anaplastic phenotype. 

Our long-term goal is to develop effective adjuvant therapy for advanced (recurrent or metastatic) and anaplastic thyroid cancer. 

Our preliminary results from thyroid cancer cell lines suggest that anaplastic thyroid cancer expresses more angiogenesis and extracellular matrix genes at higher levels. Therefore, we have chosen to examine the genetic profile of advanced thyroid cancer, paying particular attention to expression patterns of angiogenesis and ECM-related genes in an attempt to identify patients at risk for metastasis and poor outcome. 

Ras and Raf pathways appear to be targets for therapeutic manipulation in thyroid cancer, because thyroid cancers are unique in harboring mutations of all three isoforms of the oncogenic Ras, and many anaplastic thyroid cancers have Raf mutations.

Endothelial Dysfunction

Vascular endothelial injury is the hallmark of a diverse array of diseases including reperfusion injury, post-traumatic systemic inflammation (SIRS), transplant rejection, atherosclerotic complications, and tumor angiogenesis. Collectively, these diseases represent a major public health problem with significant ramifications for patients, physicians, and the health care system. 

The endothelial (EC) response to mediators of inflammation includes loss of adherens junctions, cytoskeletal rearrangement, and intercellular gap formation. While the consequences of these changes are well described, (fluid and protein transudation, leukocyte extravasation, and organ dysfunction), the intracellular events which lead to these functional derangements are unclear. Acquisition of knowledge regarding these events is important because it will allow targeted modulation of endothelial function while preserving other aspects of endothelial signaling.

Our long-range goal is to understand the dominant signaling pathways that regulate endothelial signaling. Our central hypothesis is that endothelial (EC) signaling by growth factors and cytokines ultimately results in junctional phosphorylation events and endothelial cytoskeletal rearrangement; both events together weaken the adherens junction, causing junctional dissociation and intercellular gap formation. We hypothesize that similar events are also responsible for the early phase of endothelial dissociation, proliferation, and migration during angiogenesis.

Accumulating evidence implicates endogenous oxidants as intracellular second messengers during cytokine-signaling. Our observations also suggest that human venous endothelial cells possess the ability to transiently produce oxidants in response to growth factors. Initial experiments in our laboratory suggest that the NAD(P)H oxidase system plays a prominent role in endothelial oxidant production in response to cytokines. Since antioxidants are currently in wide clinical use, therefore, identification of specific intracellular oxidant-sensitive targets could accelerate the development of novel antioxidant therapies.