Lysophosphatidic Acid Aberrancies and Hepatocellular Carcinoma: Studies in the MDR2 Gene Knockout Mouse

Abstract

Studies show that lysophosphatidic acid (LPA) reprogramming is associated with the development of hepatocellular carcinoma (HCC). This manuscript evaluates the MDR2(-/-) model of HCC as a tool to examine the role of LPA reprogramming in the initiation/progression of HCC and identify novel treatment targets. Hepatic tumors developed in MDR2(-/-) mice between 9-12 m and serum LPA levels were greater in MDR2(-/-) when compared to controls. Blocking LPA biosynthesis/signaling significantly reduced tumor burden. LPA biosynthesis/signaling plays an important role in murine MDR2(-/-) model and is potentially linked to regulation of TNFα or other cytokines that are relevant to high-risk patients.

Evaluation of 11C-Acetate and 18 F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma

“…Moreover, we have previously shown that LPA variants were able to differentiate between liver disease and patients with HCC [ 59 ]. Interestingly, these data are consistent with our current, and previous [ 6 ], studies in MDR2 −/− mice where LPA is not only elevated contemporaneous with HCC, but the LPA 20:4 and 18:2 variants are highly consistent with data from the clinical populations with HCC. Currently the precise role and mechanism connecting LPA to HCC is not fully understood.…”

“…In patients transplanted with cancer in whom the explant shows a greater disease burden than that noted on pre-transplant imaging putting them at a higher risk for cancer recurrence 11 C-acetate imaging may provide some advantage over CT or MRI when used for surveillance in post-transplant patients considered at higher risk for recurrence and in whom clinical trials of novel immunosuppressant protocols post-transplant would become relevant. The MDR2 -/- mouse model of HCC provides a murine model whereby new paradigms of HCC diagnosis and targeted therapy can be evaluated [ 6 ].…”

“…The purpose of this manuscript is to evaluate modalities of PET/CT for monitoring liver disease and HCC in MDR2 −/− mice in order to facilitate future studies aimed at exploring experimental treatments. Previous experiments using MDR2 −/− mice have relied upon macroscopic measurements of tumor burden [ 6 ]; however, using this approach definitive assessments are only feasible at study termination, and therefore do not provide continual monitoring of disease progression and therapeutic response during the emergence and growth of HCC.…”

“…MDR2 is a membrane-associated protein linked to lipid transportation and is increased in HCC cell lines and tumors [ 4 , 5 ]. Previous studies have demonstrated in vitro MDR2 expression is increased in response to chemotherapeutic agents and that HCC develops spontaneously in MDR2 −/− mice [ 6 – 11 ]. More recently we have shown that HCC tumor burden can be reduced by administration of the commercially available LPA biosynthesis/signaling inhibitor BrP-LPA [ 6 ] and confirmed the use of MDR2 −/− mice as a model for clinical pathologies [ 12 – 16 ].…”

“…Previous studies have demonstrated in vitro MDR2 expression is increased in response to chemotherapeutic agents and that HCC develops spontaneously in MDR2 −/− mice [ 6 – 11 ]. More recently we have shown that HCC tumor burden can be reduced by administration of the commercially available LPA biosynthesis/signaling inhibitor BrP-LPA [ 6 ] and confirmed the use of MDR2 −/− mice as a model for clinical pathologies [ 12 – 16 ]. This current study builds on our use of macroscopic measurements of HCC as indicators of disease progression, and evaluates non-invasive markers and imaging in MDR2 −/− mice in order to validate tools pursuant to accurately measuring response to chemotherapeutic agents in future studies.…”