Darbepoetin-α Enhances Hepatectomy-Associated Stimulation of Colorectal Liver Metastatic Growth

Rupertus, Kathrin; Sperling, Jens; Corsten, Marcus; Scheuer, Cláudia; Nickels, Ruth M.; Schilling, Martin K.; Menger, Michael D.; Kollmar, Otto

doi:10.1097/sla.0b013e3181e33915

Cited by 12 publications

(17 citation statements)

References 47 publications

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“…By direct intraportal injection of EPO or DPO, higher local concentrations can be achieved [11]. This, however, may particularly stimulate the growth of remnant intrahepatic tumor cells, as demonstrated after DPO treatment in nonestablished and established experimental colorectal liver metastases [11,12]. However, these studies did not clarify whether the increased tumor growth after DPO was only due to its local application with selective intrahepatic action.…”

Section: Discussionmentioning

confidence: 90%

“…Thus, EPO is capable of directly increasing endothelial cell proliferation and stimulating tumor angiogenesis. The angiogenic action of EPO can also be mediated indirectly via upregulation of the vascular endothelial growth factor [11,22,23]. Thus, EPO may be capable of acting systemically on tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Among the different ways of drug application, administration of EPO or DPO directly after liver resection may be preferable, assuming a higher accumulation of the drug in the remnant liver. By direct intraportal injection of EPO or DPO, higher local concentrations can be achieved [11]. This, however, may particularly stimulate the growth of remnant intrahepatic tumor cells, as demonstrated after DPO treatment in nonestablished and established experimental colorectal liver metastases [11,12].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, EPO may directly induce tumor cell proliferation, because many tumor cells and tumor cell lines express EPO receptors [11,12,19]. In vitro studies have shown that EPO activates distinct signaling pathways, including JAK2/STAT5, PI3K/Akt and Ras/ERK, thus, promoting malignant cell invasion, migration, adhesion, and colony formation [20].…”

Section: Discussionmentioning

confidence: 99%

“…Using a model of experimental colorectal liver metastases, Rupertus et al [11,12] have shown that DPO directly applied via the portal vein significantly enhances hepatectomy-associated engraftment of colorectal cancer cells in the liver. This was associated with an increase in neovascularization and cell proliferation as well as with a suppression of intratumoral leukocyte recruitment and a reduction of tumor cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Darbepoetin-α Accelerates Neovascularization and Engraftment of Extrahepatic Colorectal Metastases

Senger

Kollmar²,

Menger³

et al. 2014

Eur Surg Res

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Purpose: Erythropoietin and its analogue darbepoetin (DPO)-α have been shown to improve liver function and regeneration after partial hepatectomy (Phx). However, previous experimental studies have also shown that DPO significantly enhances Phx-induced engraftment of colorectal liver metastases by increasing neovascularization and tumor cell proliferation. Therefore, the present study analyzed whether DPO affects engraftment and neovascularization of extrahepatic colorectal metastases after major hepatectomy. Methods: Green fluorescent protein-transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Animals received a single dose of DPO (10 µg/kg body weight) at the day of tumor cell implantation (day 0). Phosphate-buffered saline-treated animals served as controls. To study whether the effect of DPO is influenced by Phx, additional animals with and without DPO treatment underwent 70% Phx at day 0. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied repetitively over 14 days using intravital fluorescence microscopy, histology and immunohistochemistry. Results: In nonhepatectomized animals, DPO significantly accelerated tumor cell engraftment and slightly enhanced tumor neovascularization. Tumor cell migration and host tissue infiltration were not affected by DPO. In hepatectomized animals, DPO slightly enhanced tumor growth and significantly accelerated tumor neovascularization, but did not affect tumor cell migration and infiltration. Conclusion: The present study indicates that DPO accelerates extrahepatic engraftment of colorectal cancer cells, most probably by stimulating the process of neovascularization.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Darbepoetin-α Accelerates Neovascularization and Engraftment of Extrahepatic Colorectal Metastases

Senger

Kollmar²,

Menger³

et al. 2014

Eur Surg Res

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Darbepoetin inhibits proliferation of hepatic cancer cells in the presence of TGF-β

et al. 2013

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Darbepoetin (DPO), an erythropoietin (EPO) derivative, was licensed in 2002 to treat patients with solid tumors suffering from chemotherapy-dependent anemia, although various tumors express EPO to improve vascularization, thus favoring tumor growth and spreading. Therefore, we wanted to investigate direct effects of DPO on the liver tumor cell lines HepG2, SkHep1, Huh-7, AKN1, HCC-T and HCC-M, as well as on primary human hepatocytes (hHeps). DPO (0-40 ng/ml) did not affect viability of hHeps, HepG2, SkHep1, AKN1, HCC-T and HCC-M cells, as determined by Resazurin conversion. However, Huh-7 cells' viability dose-dependently decreased from 5 ng/ml DPO on. Lack of LDH release into culture medium and negative DNA laddering excluded apoptosis or necrosis as the cause for the reduced Resazurin conversion. In Huh-7 cells, DPO increased the expression of p53. Interestingly, Huh-7 cells showed the highest basal TGF-β1 expression as compared to the other cell lines. Upon inhibition of TGF-β1 signaling, DPO no longer reduced viability in Huh-7 cells. On the contrary, co-incubation with TGF-β1 made the other cell lines responsive to DPO. Summarizing our data, we show that DPO reduces the growth of Huh-7 cells by up-regulation of the tumor-suppressor gene p53. This mechanism seems to be dependent on a strong TGF-β expression and corresponding signaling in these cells, as other cell lines became responsive to DPO with TGF-β1 supplementation. The knowledge of this mechanism offers great perspectives for the understanding and treatment of solid liver tumors.

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Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice

et al. 2020

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Aims The minimal-invasive transplantation of pancreatic islets is a promising approach to treat diabetes mellitus type 1. However, islet transplantation is still hampered by the insufficient process of graft revascularization, leading to a poor clinical outcome. Accordingly, the identification of novel compounds, which accelerate and improve the revascularization of transplanted islets, is of great clinical interest. Previous studies have shown that darbepoetin (DPO)-α, a long lasting analogue of erythropoietin, is capable of promoting angiogenesis. Hence, we investigated in this study whether DPO improves the revascularization of transplanted islets. Methods Islets were isolated from green fluorescent protein-positive FVB/N donor mice and transplanted into dorsal skinfold chambers of FVB/N wild-type animals, which were treated with DPO low dose (2.5 µg/kg), DPO high dose (10 µg/kg) or vehicle (control). The revascularization was assessed by repetitive intravital fluorescence microscopy over an observation period of 14 days. Subsequently, the cellular composition of the grafts was analyzed by immunohistochemistry. Results The present study shows that neither low- nor high-dose DPO treatment accelerates the revascularization of free pancreatic islet grafts. However, high-dose DPO treatment increased the blood volume flow of the transplanted islet. Conclusions These findings demonstrated that DPO treatment does not affect the revascularization of transplanted islets. However, the glycoprotein increases the blood volume flow of the grafts, which results in an improved microvascular function and may facilitate successful transplantation.

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Darbepoetin-α Enhances Hepatectomy-Associated Stimulation of Colorectal Liver Metastatic Growth

Cited by 12 publications

References 47 publications

Darbepoetin-α Accelerates Neovascularization and Engraftment of Extrahepatic Colorectal Metastases

Darbepoetin-α Accelerates Neovascularization and Engraftment of Extrahepatic Colorectal Metastases

Darbepoetin inhibits proliferation of hepatic cancer cells in the presence of TGF-β

Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice

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