Avoiding hepatic metastasis naturally: Lessons from the cotton top tamarin (Saguinus oedipus)

Abstract

Much has been written about hepatic metastasis and animal models abound. In terms of the human experience, progress in treating this final common pathway, a terminal event of many human malignancies has been relatively slow. The current thinking is that primary prevention is best served by early detection of cancer and eradication of early stage cancers by screening. Some cancers spread early in their course and the role of screening may be limited. Until relatively recently there has not been a pathfinder model that makes the evasion of this unfortunate event a reality. This review discusses such an animal model and attempts to relate it to human disease in terms of intervention. Concrete proposals are also offered on how scientists may be able to intervene to prevent this deadly progression of the cancer process.

p38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer—A Comparative Study with Humans

“…Despite detectable CEA and BGP antigens in the colonic tissues our past work suggests that there are significant changes in Callitrichidae CEA, CEA liver receptors, and glycosylation that makes the liver an “infertile field” [ 7 ]. In addition, BGP is not expressed in the CTT liver (but is found in the gallbladder wall) [ 33 ]. BGP, a downstream effector of VEGF, clearly has detectable tissue levels in the colon tissue but apparently absent in the liver depriving metastatic cells of crucial angiogenic support.…”

“…Our analyses were strengthened by the comparison of human CRC p38γ to preclinical models including the CTT. The CTT is known as a natural animal model for inflammatory bowel disease complicated by CRC [ 9 , 33 , 45 ]. We used the CTT liver as a pp38γ protein negative control as it evades hepatic metastasis, which is dependent on p38γ phosphorylation, at least in the HCC scenario [ 20 ].…”

“…The CTT is an endangered species and access to tissues are severely limited, which does not currently allow p38γ for comparisons in colonic tissue. Overall, we have posited several potential mechanisms by which the CTT evades liver metastasis [ 7 , 33 ] and the absence of hepatic pp38γ may be an additional novel mechanism. Given the predilection of humans for liver spread of CRC, our results showing enhanced phosphorylation of p38γ in CRC patients suggest that p38γ is a prometastatic protein in CRC.…”

“…In comparison to the CTT that do not express BGP in liver tissues, the lack of effect of the p38 MAPK inhibition suggests that BGP has a separate role in human liver metastasis which remains to be fully defined. Since BGP is a downstream effector for VEGF and important in establishing a vital blood supply for liver metastases [ 33 ], we postulate that as long as BGP remains a structural biliary canalicular component it is not able to act as a VEGF effector. However, we have shown that BGP does translocate to the hepatocyte cytoplasm in patients with metastasis, thus allowing it to potentially promote liver metastases [ 7 ].…”

“…However, the results of this study support the role of this MAPK in liver metastasis as we detected an increased pp38γ activation in CRC patients along with a lack of pp38γ in animals that do not develop CRLM. Indeed, the absence of pp38γ in extracts of CTT liver and common marmoset may provide a potential 6th mechanism by which the CTT evades liver metastasis [ 7 , 33 ]. A possible 7th mechanism may be the lack of blood group substance expression of the sialylated phenotype.…”