JCI table of contents, July 1, 2005
Transplantation of sperm stem cells restores fertility after chemotherapy
While more than 70% of patients survive childhood leukemia, curative chemotherapy can often irreversibly impair the formation of spermatozoa, causing infertility in males. Currently, the only established clinical option for the preservation of fertility in leukemia patients is to bank sperm before treatment commences. However, as mature germ cells do not develop until the onset of puberty, children are unable to later benefit from such assisted reproductive techniques. Although the transplantation of one's own germ cells after chemotherapy holds promise for restoring fertility, a major hurdle has been the risk of contamination by leukemic cells, which may induce relapse.
Now, in a study appearing online on June 16 in advance of print publication in the July 1 issue of the Journal of Clinical Investigation, Akira Tsujimura and colleagues from Osaka University describe a way in which healthy germ cells, including spermatogonial stem cells, can be distinguished and completely separated from leukemic cells in mice, and then harvested and preserved. These cells were then transplanted into the gonads of healthy recipient mice previously exposed to chemotherapeutic agents. The transplanted germ cells successfully colonized and were able to produce healthy progeny. The successful birth of offspring of recipient mice, without the transmission of leukemia to the recipient, suggests the potential of autotransplantation of carefully sorted germ cells in order to treat the infertility that arises as a result of anticancer treatment for childhood leukemia.
A number of issues surrounding the harvest of such material from prepubertal children with leukemia, that could be safely stored and retransplanted into chemotherapy-damaged testes, have not yet been solved. These include: (i) the harvest of sufficient numbers of healthy germ cells, without significant tissue loss; (ii) careful isolation of germ cells, including stem cells, from the population of malignant cells to avoid relapse; and (iii) ensuring that isolated germ cells are able to undergo normal spermatogenesis. However, this overall approach may hold great potential for the treatment of infertility following recovery from childhood leukemia.
TITLE: Transplantation of spermatogonial stem cells isolated from leukemic mice restores fertility without inducing leukemia
Osaka University Graduate School of Medicine, Osaka, Japan
Phone: 81-6-6879-3531; Fax: 81-6-6879-3539; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24189
Claudin-1: a potential biomarker for colon cancer progression
Disruption of proteins expressed at the junctures between cells (known as tight junctions) is a hallmark of cancer cell invasion and spread (metastasis). Recent studies have shown that changes in the family of tight junction proteins known as claudins occur during tumor initiation and growth, however no causal link between claudin expression and cancer has been demonstrated.
In a study appearing online on June 16 in advance of print publication in the July 1 issue of the Journal of Clinical Investigation, Punita Dhawan and colleagues from Vanderbilt University report increased expression of claudin-1 in human primary colon carcinomas and metastases. They also found that instead of being normally expressed in the cell membrane, claudin-1 was instead located in the colon cancer cell nucleus and cytoplasm. Those cancer cells that metastasized from the primary tumor site were found to express the highest levels of claudin-1 and also exhibited a greater degree of claudin-1 mislocalization. Using genetically manipulated colorectal cancer cells, the authors demonstrate a role for claudin-1 in the regulation of cellular transformation, tumor growth, and spread and identify, in part, the cellular pathways involved in claudin-1 overexpression.
These observations raise the possibility that claudin-1 may be exploited as a potential biomarker for colon cancer progression and may also provide new opportunities for therapeutic invention.
TITLE: Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer
Vanderbilt University Medical Center, Nashville, Tennessee, USA
Phone: (615) 322-4755; Fax: (615) 322-6174; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24543
Chronic lymphocytic leukemia tampers with T cells
The development of cancer is associated with a failure to mount an effective immune response against the tumor cells. However, we have yet to fully understand how cancer cells perturb normal T cell activity. In a study appearing online on June 16 in advance of print publication in the July 1 issue of the Journal of Clinical Investigation, John Gribben and colleagues from Queen Mary University of London, compare the global gene expression patterns of T cells from patients with untreated B cell chronic lymphocytic leukemia (B-CLL) to those of the T cells of age-matched, healthy individuals. In B-CLL patients, the authors observed altered expression of genes involved in the differentiation of CD4 T cells, and of genes involved in the structure, intracellular movement of molecules, and toxicity of CD8 T cells. They also showed that these changes were induced only upon direct contact of B-CLL cells and healthy T cells. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients should allow researchers to assess ways in which to repair these defects, in order to support the anti-tumor immune response.
TITLE: Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells
John G. Gribben
Queen Mary University of London, United Kingdom
Phone: 44-207-882-6126; Fax: 44-207-882-6004; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24176
Ezrin eager to block blood vessel growth
Tumor necrosis factor–alpha (TNF-alpha) modulates the proliferation of endothelial cells that line the interior of blood vessels and are hence at the center of new vessel growth (a process known as angiogenesis). However, just how TNF-alpha achieves this effect on endothelial cells is unclear.
In a study appearing online on June 16 in advance of print publication in the July 1 issue of the Journal of Clinical Investigation, Douglas Losordo and colleagues from Tufts University show that TNF-alpha induces the expression of a protein known as ezrin, which binds to corepressor elements in the promoter of cyclin A – an important cell cycle regulator in endothelial cells – and thereby prohibits cyclin A expression and endothelial cell proliferation. The authors go on to show that blockade of ezrin leads to enhanced endothelial cell proliferation and new blood vessel growth in a mouse model of hind limb injury.
The studies suggest that ezrin activation and function represent novel therapeutic targets for diseases or conditions in which the proliferation of endothelial cells and/or the growth of new blood vessels play a significant role.
TITLE: The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha–induced transcriptional repression of cyclin A
Douglas W. Losordo
Tufts University School of Medicine, Boston, Massachusetts, USA
Phone: (617) 789-3474; Fax: (617) 789-6362; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=22849
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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