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Elucidating the Effects of Interstitial Fluid Flow on Hepatocellular Carcinoma Invasion
Start Date: 6/1/2017Start Time: 11:00 AM
End Date: 6/1/2017End Time: 1:00 PM

Event Description
BIOMED PhD Thesis Defense

Title:
Elucidating the Effects of Interstitial Fluid Flow on Hepatocellular Carcinoma Invasion

Speaker:
Arpit Shah, PhD Candidate, School of Biomedical Engineering, Science and Health Systems

Advisor:
Adrian C. Shieh, PhD, Assistant Professor, School of Biomedical Engineer, Science and Health Systems

Abstract:
Over the last two decades, with advancements in the research, detection, and treatment of all cancer types in the United States, resulting in an overall 23% decrease in cancer related deaths, liver cancer has gone against this trend, possessing an increased death rate. Globally, hepatocellular carcinoma (HCC), the most common form of liver cancer, ranks as the second leading cause of cancer related deaths with approximately 788,000 deaths annually. In recent years, much emphasis has been placed on understanding the process of HCC cell invasion; however, it has become apparent that the progression of this disease is not solely dependent on just the cancer cells or biological factors, but also on their interaction with the tumor microenvironment. A significant number of studies have shown that changes in biomechanical forces within the tumor microenvironment can alter cancer progression. Previous research has demonstrated that interstitial fluid flow (IFF), one of the biomechanical forces that is altered during tumor growth, can promote cancer cell invasion. The overall goal of this study was to develop a fundamental and mechanistic understanding of how IFF effects HCC invasion.

Utilizing our 3D in vitro flow invasion assay, we demonstrate CXCR4/CXCL12-dependent autologous chemotaxis as a significant mechanism involved in IFF-induced invasion of HCC cells. Additionally, MEK/ERK signaling is identified as a significant contributor to IFF-induced invasion, but one that is independent of the CXCR4/CXCL12-autologous chemotaxis mechanism. Increased matrix metalloproteinase (MMP) expression is a hallmark for cancer progression and poor prognosis. Biomechanical forces have been observed to increase the secretion of these proteolytic enzymes, which promote extracellular matrix degradation and tumor cell invasion. We observed increased MMP-9 and MMP-2 activity in HCC cells exposed to IFF. These findings indicate multiple mechanisms are at play in HCC flow-induced invasion.

Finally, by modifying our 3D in vitro flow invasion assay, we examined IFF in a progressive HCC disease model, where HCC cells were embedded in a stiff matrix. The increase in matrix stiffness is a result of tumor growth, shown to disturb the mechanical forces and biochemical signaling that occurs in the microenvironment, effectively promoting disease progression. HCC also possesses a very unique disease profile and risk factors; nearly 80% of HCCs occur from patients who suffer from chronic fibrosis or cirrhosis, where inflammation and hepatic wound-healing response attributes to the hepatocarcinogenesis. Many studies have observed cellular behavior of hepatocytes and HCC cells in a stiff matrix; however, none have observed the effect of IFF and a stiff microenvironment in HCC cells. Our findings confirm a synergistic relationship between IFF and matrix stiffness on HCC cell invasion. These findings suggest for the first time that IFF increases HCC cell invasion through multiple mechanisms, ultimately adding to the mounting evidence of how biomechanical forces in the tumor microenvironment influence cancer progression.
Contact Information:
Name: Ken Barbee
Phone: 215-895-1335
Email: barbee@drexel.edu
Arpit Shah
Location:
Bossone Research Center, Room 709, located at 32nd and Market Streets.
Audience:
  • Undergraduate Students
  • Graduate Students
  • Faculty
  • Staff

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