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

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.

Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD

“…Disease-induced cellular senescence has been shown within the kidney and other organs. 128–130 Increased levels of cellular senescence have been reported in patients with hypertension, 131 in tubular cells of patients with IgA nephropathy 132 and in type 2 diabetes, 133 where they correlate with severity of renal disease. Our own data demonstrate growth-arrested tubular cells to be predictive of the development of CKD subsequent to AKI.…”

DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression

“…In this respect, mouse models of metabolic syndrome with NAFLD reveal features of accelerated aging, impaired regeneration, and an increased incidence of HCC(2, 3). Interventions to clear senescent hepatocytes in a neoplastic-prone tissue microenvironment delay the emergence of HCC in rats (4). Cellular senescence can thus regulate tumor suppression, as well as contribute to age-related loss of tissue function through the secretion of multiple proinflammatory molecules, such as IL6 and IL8, as part of a senescence-associated secretory phenotype (SASP; ref.…”

SMT and TOFT: Why and How They are Opposite and Incompatible Paradigms

“…Indeed, even when transplanting highly metastatic cancer cells, no tumors arise when they are introduced into an embryo field (Lee et al 2005). Additionally, several studies have highlighted that the likelihood of successful tumor transplant is highly dependent on the age of microenvironmental stroma (Maffini et al 2005;Marongiu et al 2014). Usually, this evidence is either dismissed by SMT supporters, or else it is ignored being considered an ''odd'' exception.…”