Cancer Cell Biology Training Program

Isaac Chan

Preceptor - Al Baldwin, PhD

Hepatocellular carcinoma (HCC) accounts for up to 1 million deaths a year and is the third leading cause of cancer deaths worldwide [1]. Cirrhosis, a consequence of chronic liver injury states such as alcoholism, non-alcoholic fatty liver disease, or viral hepatitis, is the single largest risk factor for HCC [2]. Patients with compensated liver cirrhosis have a 3-4% annual risk of HCC and as many as 56% HCC patients have undiagnosed cirrhosis. Treatment of HCC often involves surgical resection, but patients are faced with high recurrence rates, suggesting that cells outside the tumor play an important role in tumorigenesis [3]. In spite of its great importance, the role of the microenvironment in the tumorigenesis of HCC is unknown.


The development of HCC requires the acquisition of multiple mutations leading to dysgregulation of signaling critical for cell growth and fate, occurring in the context of response to chronic injury [4, 5]. Work from our laboratory has shown that chronic liver injury inhibits replication of surviving mature hepatocytes and activates normally dormant mechanisms that promote the expansion and differentiation of liver epithelial progenitors: As hepatocytes are exposed to injury and die, Sonic hedgehog (Shh) ligand is released in exosomes and activates Hh pathway activity in responsive cells found in progenitor and myofibroblastic compartments, mobilizing them to repopulate the liver
[6]. Signals from the myofibroblastic components can then exert an influence on the environment: Our lab has shown that myofibroblasts induce epithelial-to-mesenchymal transitions (EMT) in ductular epithelium and through the Hh signaling, inflammatory cells are recruited [7-13]. Cirrhosis arises when the activation of these myofibroblastic compartments become dysregulated and excessive fibrous matrix is produced [14]. Thus, we hypothesize it is from within this Hh rich microenvironment that HCC develops and progresses.

The Hedgehog pathway and Shh ligand itself has been shown to be key component in hepatocellularcarcinogenesis. Our lab has demonstrated Smoothened (Smo) mutations in various cell lines of HCC and other labs have further shown Hh to be a viability pathway and associated with chemoresistance in HCC [15-19]. We have also shown compelling evidence that Hh activity even occurs in the peritumor stroma of HCC and this observation is confirmed with studies indicating that Hh works in a paracrine fashion to promote tumorigenesis in vivo [17]. Despite this body of evidence demonstrating the importance of the Hh pathway in HCC and in the crosstalk between tumors and the stroma, the exact mechanism remains a mystery. My project focuses on understanding the role of Hh signaling in the tumorigenesis of HCC through paracrine signaling between stroma and tumor.