Spotlight

Abstract

Nawashiro et al., pages 484–492 Malignant gliomas are the most common brain tumors with the least favorable prognosis in human cancer biology. New molecular targets for therapeutic intervention are needed to control the highly invasive tumor growth and to prevent recurrence after surgical excision. In this issue, Nawashiro and colleagues identified a new molecular marker abundantly expressed on glioblastoma and low-grade astrocytoma cells. They performed immunohistochemistry on tumor samples isolated from 60 individuals with primary astrocytic tumors. They found that the expression of the L-type amino acid transporter 1 (LAT1) was specifically upregulated on the surface of glioma cells and that high expression of LAT1 correlated with poor prognosis in patients. Overall, expression of LAT1 was the second strongest predictor of outcome, independent of other variables. LAT1 is known to transport neutral amino acids with branched or aromatic side chains and exhibits a high affinity for several nutritionally essential amino acids such as leucine, isoleucine, valine and phenylalanine. In healthy tissue LAT1 is only transiently expresssed and rapidly degraded. The authors speculate that high LAT1 expression is required to supply the rapidly proliferating tumor cells with essential amino acids. To test this model, they treated C6 glioma cells with a pseudosubstrate inhibitor of the transport system, 2-aminobicyclo-2(2,2,1)-heptane-2-carboxylic acid (BCH). At millimolar concentrations BCH inhibited the growth of glioma cells in vitro and reduced the tumor size in rats implanted with the glioma cells in vivo. These results support a model in which LAT1 plays an important role in the growth of malignant gliomas and represents a new target for the experimental treatment of brain tumors Eliassen et al., pages 493–500 Antimicrobial peptides induce cell death in transformed, but not in nontransformed cells. While the mechanism of action against prokaryotic cells has been widely investigated, not much is known about their effects in tumor cells. One possibility is that membranes of cancer cells, such as prokaryotic cells, have a higher content of anionic phospholipids that are targeted by positively charged residues in the peptides. Eliassen and colleagues focussed on bovine lactoferricin (LfcinB), a 25 amino acid basic peptide with proven antimicrobial and antitumor properties. They found that it displayed selective cytotoxicity in a panel of neuroblastoma cell lines as compared to nontransformed fibroblasts. Interestingly, cell lines harboring a known amplification of the MYCN oncogene were more sensitive to LfcinB, underlining the clinical potential in cancer therapy for the peptide. LfcinB injections also reduced the growth of SH-SY-5Y neuroblastoma xenografts in nude rats without significant side effects. Experiments with fluorescence-labeled peptide demonstrated that LfcinB directly targeted and destabilized mitochondrial membranes and led to the cleavage of caspases 6, -7 and -9 followed by cell death. Mitochondria are characterized by a highly negative surface due to the cardiolipin content of their outer membrane. The affinity of LfcinB for this organelle is therefore not surprising. However, the selective cytotoxicity of LfcinB in tumor cells points to specific alterations in the composition of mitchondrial membranes in cancer cells Prowse et al., pages 556–562 Ovarian cancer is the deadliest of all gynecological cancers and ranks fourth in cancer deaths among middle-aged women. More than 90% of ovarian cancers are epithelial in origin and can be divided into serous, mucinous, endometrioid, clear cell and undifferentiated types. Endometrioid and clear cell subtypes have been associated with the benign disease endometriosis. This disease is characterized by the presence of endometrial-like epithelium and stroma in extra-uterine sites such as the ovaries and the peritoneum. Circumstantial evidence that endometriosis is a precursor to endometriosis-associated ovarian cancer (EAOC) has been accumulating for many years. However, it is still unclear whether endometriosis is a precursor to EAOC, or whether there is an indirect link between the two conditions because they share the same risk factors, such as earlier menarche, more regular periods, shorter cycle length and lower parity. To demonstrate clonal progression between the two events, Prowse and colleagues analyzed 10 cases of EAOC with coexisting endometriosis for the existence of common molecular genetic alterations. They report that out of 63 loss of heterozygosity (LOH) events detected in the carcinoma samples, 22 were also detected in the corresponding endometriosis samples. Interestingly, no marker showed LOH in the endometriosis sample alone. These observations provide an elegant molecular demonstration that endometriosis is a direct precursor to EAOC.