Differential Growth: From Carcinogenesis to Liver Repopulation

Laconi, Ezio

doi:10.1016/s0002-9440(10)64741-4

Cited by 20 publications

(18 citation statements)

References 26 publications

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“…The analysis of recently developed transplantation systems has convincingly demonstrated that, when the growth capacity of endogenous hepatocytes is impaired, transplanted normal cells can selectively expand in the form of clonal clusters (Grompe et al ., 1999;Laconi, 2000;Laconi & Laconi, 2002). Based on this evidence, we interpret the growth advantage of transplanted hepatocytes in the liver of aged animals as a reflection of a decreased proliferative potential of Fig.…”

Section: Discussionmentioning

confidence: 72%

Aging is associated with increased clonogenic potential in rat liver in vivo

et al. 2006

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SummaryCancer increases with age and often arises from the selective clonal growth of altered cells. Thus, any environment favoring clonal growth per se poses a higher risk for cancer development. Using a genetically tagged animal model, we investigated whether aging is associated with increased clonogenic potential. Groups of 4-, 12-, 18-, and 24-month-old Fischer 344 rats were infused (via the portal vein) with 2 × × × × 10 6 hepatocytes isolated from a normal syngenic 2-month-old donor. Animals deficient in dipeptidylpeptidase type IV (DPP-IV-) enzyme were used as recipients, allowing for the histochemical detection of injected DPP-IV + cells. Groups of animals were sacrificed at various times thereafter. No growth of DPP-IV + transplanted hepatocytes was present after either 2 or 6 months in the liver of rats transplanted at young age, as expected. In striking contrast, significant expansion of donor-derived cells was seen in animals transplanted at the age of 18 months: clusters comprising 7-10 DPP-IV+ hepatocytes/crosssection were present after 2 months and were markedly enlarged after 6 months (mean of 88 ± ± ± ± 35 cells/cluster/ cross-section). These results indicate that the microenvironment of the aged liver supports the clonal expansion of transplanted normal hepatocytes. Such clonogenic environments can foster the selective growth of pre-existing altered cells, thereby increasing the overall risk for cancer development associated with aging.

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Section: Discussionmentioning

confidence: 72%

Aging is associated with increased clonogenic potential in rat liver in vivo

et al. 2006

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“…13,18 A key component in this model is the persistent block imposed by RS on endogenous hepatocyte cell division, which allows for the selective expansion of transplanted cells. 13,19 Consistent with this interpretation, PH was found to be essential to achieve massive liver replacement within a few months after transplantation. However, it was repeatedly observed 13,20 that a low, but significant extent of repopulation (up to ϳ15% within 6 weeks) 20 was also present in animals not receiving PH.…”

Section: 5mentioning

confidence: 65%

Massive Liver Replacement by Transplanted Hepatocytes in the Absence of Exogenous Growth Stimuli in Rats Treated with Retrorsine

Laconi¹,

Pillai²,

Porcu³

et al. 2001

The American Journal of Pathology

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A strategy for hepatocyte transplantation was recently developed whereby massive replacement of the recipient liver is achieved after a combined treatment with retrorsine, a pyrrolizidine alkaloid, and partial hepatectomy. We now investigated whether liver repopulation could occur in this animal model in the absence of any exogenous growth stimuli (eg, partial hepatectomy) for the transplanted cells. Dipeptidyl-peptidase type IV-deficient (DPPIV ؊ ) rats were used as recipients. Rats were given two injections of retrorsine (30 mg/kg each, 2 weeks apart), followed by transplantation of 2 ؋ 10 6 hepatocytes isolated from a normal, syngeneic, DPPIV ؉ donor. At 2 weeks after transplantation, clusters of DPPIV ؉ hepatocytes occupied 3.3 ؎ 0.9% of host liver, increasing to 38.2 ؎ 6.3% at 2 months, and to 65.9 ؎ 8.8% at 5 months. By 1 year, >95% of the original hepatocytes were replaced by donor-derived cells. Serum parameters related both to hepatocyte function and integrity (including glucose, bilirubin, total proteins, cholinesterase, alanine aminotransferase, and alkaline phosphatase) were in the normal range in retrorsine-treated and repopulated animals. These results provide further insights toward developing strategies for effective liver repopulation by transplanted hepatocytes with reduced toxicity for the host and potential clinical applicability. Transplantation of isolated hepatocytes is increasingly being considered as a possible alternative to whole organ replacement, which is currently the only available therapy to treat both inherited and acquired end-stage liver disease.

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“…The above-referenced similarities in the biological response of normal and nodular hepatocytes are intriguing (40). However, at least two main differences were evident in the phenotypic behavior of the two cell populations.…”

Section: Discussionmentioning

confidence: 98%

A growth-constrained environment drives tumor progression in vivo

Laconi

Pani

Pillai

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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We recently have shown that selective growth of transplanted normal hepatocytes can be achieved in a setting of cell cycle block of endogenous parenchymal cells. Thus, massive proliferation of donor-derived normal hepatocytes was observed in the liver of rats previously given retrorsine (RS), a naturally occurring alkaloid that blocks proliferation of resident liver cells. In the present study, the fate of nodular hepatocytes transplanted into RS-treated or normal syngeneic recipients was followed. The dipeptidyl peptidase type IV-deficient (DPPIV ؊ ) rat model for hepatocyte transplantation was used to distinguish donor-derived cells from recipient cells. Hepatocyte nodules were chemically induced in Fischer 344, DPPIV ؉ rats; livers were then perfused and larger (>5 mm) nodules were separated from surrounding tissue. Cells isolated from either tissue were then injected into normal or RS-treated DPPIV ؊ recipients. One month after transplantation, grossly visible nodules (2-3 mm) were seen in RS-treated recipients transplanted with nodular cells. They grew rapidly, occupying 80 -90% of the host liver at 2 months, and progressed to hepatocellular carcinoma within 4 months. By contrast, no liver nodules developed within 6 months when nodular hepatocytes were injected into the liver of recipients not exposed to RS, although small clusters of donor-derived cells were present in these animals. Taken together, these results directly point to a fundamental role played by the host environment in modulating the growth and the progression rate of altered cells during carcinogenesis. In particular, they indicate that conditions associated with growth constraint of the host tissue can drive tumor progression in vivo.

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Differential Growth: From Carcinogenesis to Liver Repopulation

Cited by 20 publications

References 26 publications

Aging is associated with increased clonogenic potential in rat liver in vivo

Aging is associated with increased clonogenic potential in rat liver in vivo

Massive Liver Replacement by Transplanted Hepatocytes in the Absence of Exogenous Growth Stimuli in Rats Treated with Retrorsine

A growth-constrained environment drives tumor progression in vivo

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