Research Areas

The Role of Neuroendocrine Cells in Prostate Progression

Neuroendocrine (NE) differentiation of prostate epithelial cells has been implicated in progression of the later stages of prostate cancer (see review, Deeble, et. al., in Recent Research Developments in Endocrinology, 2001).  In recent literature, numerous differentiation agents for prostate neuroendocrine cells have been identified.  We and others have demonstrated that agents which activate the PKA signaling pathway such as epinephrine (Epi) and isoproternol (Isop), interleukin (IL)-1, IL-2, IL-6, and serum/androgen deprivation all induce some level of phenotypic NE differentiation in LNCaP prostate tumor cells.  We have focused on PKA and IL-6 mediated differentiation of LNCaP prostate carcinoma cells. 

We have published a paper showing that physiologic and pharmacologic agents that activate the PKA pathway are capable of inducing a reversible phenotypic NE differentiation in LNCaP cells (Cancer Research, 1999).  Furthermore, we have established PKA as being the critical component in the differentiation process (The Journal of Biological Chemistry, 2000).  PKA is both necessary and sufficient for NE differentiation in response to agents such as Epi and Isop.  Continuing work will study the secretory factors in the conditioned media from these stable cell lines.

In the introduction of our manuscript published in Molecular and Cellular Biology (2001), we comment on the propensity for prostate tumor cells to metastasize specifically to bone and lymph systems.  The metastasis often occurs after deceptively successful androgen ablation therapy for a primary prostate tumor.  Current therapies are designed to eradicate incapsulated, androgen dependent tumors.  However, in a high percentage of cases, prostate cancer will recur in the androgen independent stage 5-10 years after first presentation.  Published reports have shown that anti-androgen therapy might select for NE cells and enhance tumor metastases years after first presentation.  We hypothesize that selection of bone and lymph nodes as primary sites of metastasis occurs due to the high levels of IL-6 at these sites.  In combination with stress responses to the tumor and subsequent therapies, differentiation factors that normally have no effect on prostate tumor cells may allow growth of androgen independent prostate cells in a new environment.    

We believe neuroendocrine cells play a role in prostate cancer progression to androgen independence by secreting neuropeptide factors that effect the growth, survival and mobility of prostate tumor cells.  Current anti-androgen therapies may select for NE cells and these NE cells may also arise preferentially at areas with NE differentiation agents at high concentrations.  We have set out to identify factors and signaling events that regulate the acquisition of a NE phenotype and, additionally, molecules secreted by prostatic NE cells.  We hope to determine the physiologic characteristics of NE differentiation.  These observations will help us to determine the impact of NE cells on prostate cancer progression.

Inhibition of SMC Differentiation in Prostate Tumor Blood Vessels – Implications:

Blood vessels formed during tumorigenesis are dissimilar to those formed during normal vasculogenesis and angiogenesis.  However, tumor growth and metastatic potential are critically dependent on this tumor vascularization.  Tumor vasculature is highly disorganized and contains tortuous and dilated vessels with uneven diameter.  Excessive branching and shunts in tumor vessels produce blood flow characterized as “chaotic.”  Despite tremendous efforts studying endothelial cells at the molecular, cellular and whole tissue levels, surprisingly little is known about the smooth muscle layer of the vascular system in human tumors.  Mural cells, including pericytes and smooth muscle cells (SMC’s), are classified as contractile cells that serve to stabilize the vessel wall.  Contact of these cells with endothelial cells has been suggested to promote endothelial cell survival and to inhibit endothelial cell proliferation.  Interestingly, endothelial tubes formed in tumors that invest normally with SMC’s are thought to be impermeable to the escape of cancer cells.  My research will focus on the effects that tumor cells have on the differentiation and investment profiles of SMC’s.  Cell culture models in which SMC’s exposed to tumor cells and endothelial cells under a variety of different experimental conditions will help us to understand why blood vessels in tumors develop abnormally.  Mouse models for cancer progression exist and will be utilized in combination with smooth muscle differentiation pathway-deficient transgenic animals to characterize effects on tumor growth and metastasis.  This combination of in vitro and in vivo work will provide insight into the understudied area of SMC investment of tumor vasculature.