Abstracts of Current Projects

Elucidating the effect of chronic liver inflammation on colorectal cancer metastatic dissemination. Outgrowths of disseminated metastases remain the primary cause of mortality in cancer patients; however, molecular and cellular mechanisms regulating metastatic spread remain partially elusive. It is estimated that approximately 50% of colorectal cancer (CRC) patients develop liver metastases. Recently published clinical studies have shown that colorectal liver metastasis (CRLM) is less frequent in patients with fatty liver, hepatic cirrhosis or chronic hepatitis B and C virus infection. The proposed research is designed to take a different perspective on this complicated process and to elucidate the pre-existing heterogeneous biological microenvironment in which the liver is less permissive to support metastases establishment and the factors which play a role in this. By using Mdr2-ko mice with our already established CRLM model we will be able to shed light on these complex molecular and cellular interactions. Our preliminary data demonstrates that the existence of a chronic hepatic inflammatory background in mice proactively obstructs CRLM dissemination at the age of two month while proactively mediates CRLM at the age of five months. Our central hypothesis is that the pre-existing hepatic microenvironment can alter liver metastatic seeding. The proposed research is designed to elucidate the unexplored aspects of the variable hepatic environments in facilitating or arresting metastatic disease. In order to address this complex issue, a multidisciplinary approach is undertaken involving analyses of liver samples from the different pre-existing hepatic scenarios (RNA sequencing, cytokine array etc.), cell analysis, intravital imaging and cell population manipulations.  

Liver regenerative process alterations as a consequence of bleeding and transfusion of red blood cells with different storage time: fresh vs. "aged". Liver regeneration, a process that rapidly compensates for the acute loss of liver parenchyma, plays a critical role in patients requiring large liver resections. These operations are frequently associated with massive blood loss with subsequent blood transfusion. Concerns have been raised about the safety and efficacy of transfusing stored blood. Previously, in a rat model of acute bleeding followed by blood resuscitation we found that whereas the transfusion of fresh blood improved liver outcome, transfusion of blood stored for 7 days exacerbated liver injury (Crit Care Med, 2013). Thus avoiding further liver injury induced by the transfusion of aged blood in liver surgeries is of paramount clinical importance. Our currently ongoing study, in a rat model of PHx, revealed that acute bleeding during PHx delays and attenuates liver regeneration. Moreover, with bleeding the mode of liver regeneration is altered from hepatocytes proliferation to hypertrophy (FASEB J, 2017). Furthermore, our preliminary results demonstrate that transfusion with fresh RBCs restored liver regeneration capacity following PHx and bleeding, while stored RBCs administration impedes the process and alters the pattern of liver regeneration causing further liver injury. Our current research goal is to further elucidate the underlining molecular pathways involved in the altered regenerative process due to "aged" blood transfusion. The results of this study may lead to better understanding of the liver regeneration process under pathological conditions.