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Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma.

Marongiu F, Serra MP, Sini M, Angius F, Laconi E - Aging (Albany NY) (2014)

Bottom Line: Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions.At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group.Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Unit of Experimental Medicine, University of Cagliari, 09124 Cagliari, Italy.

ABSTRACT
Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.

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The development of HCC in rats exposed to DENA+RS and killed after one year. Panel A: macroscopic appearance, with withish-grey lesions displaying prominent vasculature; panel B: trabecular HCC with discrete cellular pleomorphism (100x).
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Figure 1: The development of HCC in rats exposed to DENA+RS and killed after one year. Panel A: macroscopic appearance, with withish-grey lesions displaying prominent vasculature; panel B: trabecular HCC with discrete cellular pleomorphism (100x).

Mentions: As already mentioned, naturally occurring pyrrolizidine alkaloids, including RS, are known for their ability to promote the growth of early hepatic nodules in initiated rat liver [15]. However, no studies have been reported to date on the long term effects of these agents in animals previously given a carcinogen. In the present experiments, rats were administered DENA and RS (two single injections, 10 days apart), and they were killed 1 year later. As predicted, multiple pre-neoplastic and neoplastic hepatocellular lesions, ranging in size from a few mm to 2.5 cm in diameter, were observed in all animals exposed to this protocol (figure 1, panel A). Furthermore, histological analysis confirmed the pre-sence of large, advanced hepatocyte nodules in all liver samples in this group, while trabecular HCC was diagnosed in 4 out of 8 rats (figure 1, panel B).


Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma.

Marongiu F, Serra MP, Sini M, Angius F, Laconi E - Aging (Albany NY) (2014)

The development of HCC in rats exposed to DENA+RS and killed after one year. Panel A: macroscopic appearance, with withish-grey lesions displaying prominent vasculature; panel B: trabecular HCC with discrete cellular pleomorphism (100x).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927807&req=5

Figure 1: The development of HCC in rats exposed to DENA+RS and killed after one year. Panel A: macroscopic appearance, with withish-grey lesions displaying prominent vasculature; panel B: trabecular HCC with discrete cellular pleomorphism (100x).
Mentions: As already mentioned, naturally occurring pyrrolizidine alkaloids, including RS, are known for their ability to promote the growth of early hepatic nodules in initiated rat liver [15]. However, no studies have been reported to date on the long term effects of these agents in animals previously given a carcinogen. In the present experiments, rats were administered DENA and RS (two single injections, 10 days apart), and they were killed 1 year later. As predicted, multiple pre-neoplastic and neoplastic hepatocellular lesions, ranging in size from a few mm to 2.5 cm in diameter, were observed in all animals exposed to this protocol (figure 1, panel A). Furthermore, histological analysis confirmed the pre-sence of large, advanced hepatocyte nodules in all liver samples in this group, while trabecular HCC was diagnosed in 4 out of 8 rats (figure 1, panel B).

Bottom Line: Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions.At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group.Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Unit of Experimental Medicine, University of Cagliari, 09124 Cagliari, Italy.

ABSTRACT
Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.

Show MeSH
Related in: MedlinePlus