Item Details

title

Tumor Cell Marker CD117 Drives Progression and Metastasis in Prostate Cancer

author

Harris, Koran

abstract

Introduction: In this year alone over 190,000 men are expected to be diagnosed with prostate cancer. Of this approximately 32,000 men will die making it both the second most common and second leading cause of cancer related death in American men behind only skin and lung cancer respectively. Luckily when diagnosed early a 5-year survival rate of nearly 100% is achieved and about 80% of men are considered to be cancer and metastasis free after having a radical prostatectomy. However, the remaining 20% of patients will experience recurrence and metastasis often times to the bone, and the outcome of these patients is less favorable as the 5-year survival rate significantly decreases to less than 30%. Being that cancer metastasis is incurable, there is a great need to identify patients who are most likely to progress to the stage of metastasis and undergo recurrence. Current clinical practices rely on PSA screening to help diagnose and manage prostate cancer. Yet, new methods are needed to address unmet clinical needs. In the field current studies are focusing on understanding the individual steps of metastasis, in an attempt to develop methods to identify patients who have aggressive disease. One area of increased investigation, to discover the next generation of biomarkers determining this patient population, is circulating tumor cells (CTCs) as these cells have been shown to predict worse overall survival of metastatic castration resistant prostate cancer patients. Prior studies were able to identify CD117 positive CTCs in prostate cancer patients that were associated with cancer severity and biochemical recurrence suggesting that circulating CD117+ cells may be used as a method to predict cancer progression.Research question: What affect does CD117 expression and activation have on prostate cancer progression? Methods: To address this question we utilized CD117 expressing human bone tropic cell lines evaluating cell proliferation, migration, and invasion under normal, activated, and inhibited conditions. Furthermore, gene and protein analysis was conducted to evaluate cancer stemness and aggressiveness. To validate our findings in vivo serial tumor initiation studies were conducted. Metastatic microfluidic models were also employed to determine spontaneous invasion, migration and bone homing. Conclusion: Expression of CD117 induces increased proliferation, migration, and invasion. Also, CD117 expressing cells represents a cancer stem cell. Moreover, CD117 activation promotes partial EMT, prostate cancer mobility, and bone homing. Lastly, CD117 inhibition by TKI treatment is context dependent based on CD117 specificity. Future Directions: Additional, patient studies are needed to confirm that CD117 cells are in fact cancer stem cells. Further development of physiologically relevant bone metastasis models are required, to understand the mechanism initiating bone metastasis.

contributor

Kerr, Bethany A (committee chair)

Willey, Jeffrey (committee member)

Watabe, Kounosuke (committee member)

Soker, Shay (committee member)

Shiozawa, Yusuke (committee member)

date

2022-01-15T09:35:33Z (accessioned)

2023-01-14T09:30:14Z (available)

2022 (issued)

degree

Cancer Biology (discipline)

embargo

2023-01-14 (terms)

identifier

http://hdl.handle.net/10339/99395 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation