Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice.

CXCL12 and VCAM1 retain hematopoietic stem cells (HSCs) in the BM, but the factors mediating HSC egress from the BM to the blood are not known. The sphingosine-1-phosphate receptor 1 (S1P(1)) is expressed on HSCs, and S1P facilitates the egress of committed hematopoietic progenitors from the BM into the blood. In the present study, we show that both the S1P gradient between the BM and the blood and the expression of S1P(1) are essential for optimal HSC mobilization by CXCR4 antagonists, including AMD3100, and for the trafficking of HSCs during steady-state hematopoiesis. We also demonstrate that the S1P(1) agonist SEW2871 increases AMD3100-induced HSC and progenitor cell mobilization. These results suggest that the combination of a CXCR4 antagonist and a S1P(1) agonist may prove to be sufficient for mobilizing HSCs in normal donors for transplantation purposes, potentially providing a single mobilization procedure and eliminating the need to expose normal donors to G-CSF with its associated side effects.

Toxic epidermal necrolysis: review of pathogenesis and management.

Toxic epidermal necrolysis (TEN) is a severe cutaneous drug reaction with a mortality rate of approximately 30%. The hallmark of TEN is widespread epidermal sloughing due to keratinocyte apoptosis. Multiple genetic associations between TEN and specific ethnic populations have been determined. The pathophysiology of TEN has yet to be fully elucidated; however, current pathogenic models implicate Fas ligand, granulysin, and reactive oxygen species. The value of current therapies, such as intravenous immunoglobulin and corticosteroids, remains under evaluation.

Liver regeneration and tumor stimulation--a review of cytokine and angiogenic factors.

Liver resection for metastatic (colorectal carcinoma) tumors is often followed by a significant incidence of tumor recurrence. Cellular and molecular changes resulting from hepatectomy and the subsequent liver regeneration process may influence the kinetics of tumor growth and contribute to recurrence. Clinical and experimental evidence suggests that factors involved in liver regeneration may also stimulate the growth of occult tumors and the reactivation of dormant micrometastases. An understanding of the underlying changes may enable alternative strategies to minimize tumor recurrence and improve patient survival after hepatectomy.

Tumour growth stimulation following partial hepatectomy in mice is associated with increased upregulation of c-Met.

Hepatic resection is the preferred option for curative treatment of colorectal liver metastasis (CLM). However, this is associated with significant recurrence rates in both hepatic and extrahepatic sites. The upregulation of growth factors required for liver regeneration after resection is thought to stimulate the growth of micrometastases. The current study describes temporal changes in the expression of hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR) and insulin growth factor I receptor (IGF-IR) in an orthotopic mouse model of liver resection and tumour induction. Mice underwent 70% hepatectomy and induction of liver metastases through intrasplenic injection of colorectal cancer cells. Control groups included sham-operated mice and 70% hepatectomy alone. The expression levels of liver and tumour c-Met, EGFR and IGF-IR were quantified by quantitative RT-PCR at different time points. 70% liver resection stimulates tumour growth; increases the expression of c-Met within established tumours and surrounding liver parenchyma; downregulates EGFR expression and increases IGF-IR expression within the liver parenchyma. In conclusion, we demonstrate in our mouse model that major hepatectomy stimulates engraftment and growth of CLM and that this effect is probably due to the upregulation of c-Met as a result of the liver regeneration process. Liver IGF-IR may also contribute to this phenomenon through a paracrine effect on tumour growth. This study provides support for the role of c-Met in the stimulation of tumour growth after resection possibly through the promotion of tumour cell proliferation.

Gastrin is not required for liver regeneration.

BACKGROUND: Although several growth factors are known to be essential for liver regeneration, the role of gastrin remains controversial. METHODS: Liver regeneration was examined in wild-type (WT) and gastrin-deficient (gastrin KO) mice at days 2 and 10 after partial (40%) hepatectomy by measurement of liver weight. Hepatocyte proliferation and circulating gastrin concentrations were measured at the same time points by immunohistochemistry and radioimmunoassay, respectively. RESULTS: There was no significant difference in the rate of liver regeneration between gastrin KO and WT mice. Hepatocyte proliferation in both groups was increased at day 2 but had returned to baseline values by day 10. At day 2, hepatocyte proliferation in the gastrin KO mice was significantly higher than in WT animals, whereas at day 10, proliferation was significantly greater in the WT mice. The circulating gastrin concentration in the WT mice was significantly lower at day 10 than in unoperated WT animals. CONCLUSION: This study suggests that gastrin is not essential for liver regeneration after partial hepatectomy.

Liver regeneration stimulates tumor metastases.

BACKGROUND: Partial hepatectomy for patients with colorectal liver metastases is associated with a tumor recurrence rate approaching 80% post-resection. Different factors and phases associated with regeneration of the liver are implicated in tumor recurrence. This study investigates the effects of the early and late phases of liver regeneration and the impact of the degree of liver resection on stimulating tumor growth and metastasis. MATERIALS AND METHODS: Groups of mice underwent partial hepatectomy (37% or 70%) and were then challenged with colorectal liver carcinoma (CRC) tumors immediately after liver resection (early and late phase effect) or 6 days post liver resection (late phase effect). Tumor growth, degree of proliferation, tumor morphology, and the presence of extrahepatic metastases were investigated 21 days post-tumor induction. RESULTS: The late phase of liver regeneration plays a significant role in tumor stimulation and metastasis. The degree of hepatectomy also appears to be an important factor. The degree of hepatic resection significantly influences tumor growth and the extent of extrahepatic metastases, particularly in the lungs. CONCLUSIONS: Elucidation of the processes involved in the late phase of liver regeneration may assist in the development and timing of adjuvant agents to minimize tumor recurrence during this phase.