Tumors of glial origin are the most common brain tumors, and in their most malignant form, glioblastoma multiforme (grade IV), virtually incurable. The diversity of gliomas is mirrored by the number of different signaling pathways involved in the generation of these tumors; yet they all seem to have one thing in common: Essentially 100% of human glioma cell lines and fresh surgical isolates of human glioma show an alteration in PDGF signaling and the ectopic expression of PDGF-B is a reliable way to initiate and sustain malignant tumors in murine models of glioma.
Trying to determine the extent to which the developmental plasticity of targeted cells may influence their response to the transforming power of PDGF-B, Appolloni et al. overexpressed PDGF-B in a population of mouse neural progenitor cells capable of giving rise to all lineages of the future telencephalon. Despite the pluripotent nature of the transduced cells, only oligodendroglial tumors arose from the overexpression of PDGF-B. Careful lineage tracing revealed that the observed uniformity of tumor type is most likely due to PDGF-B's ability to shift the cell fate of immature embryonic progenitors toward the oligodendroglial lineage rather than selectively stimulating the proliferation of already committed oligodendrocyte precursors.
Recent advances in the understanding of the molecular mechanisms that govern oncogenesis have provided substantial progress in the treatment of many common human cancers. We have gained a better understanding of the molecular mechanisms governing gliomas, including glioblastoma multiforme, which—with a mean survival of less than a year—is one of the most aggressive human cancers.
Lynch Syndrome: A Shuffled Genome and Epigenetic Mutations
Gylling et al., pp. 2333–2340
Lynch syndrome, better known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant familial cancer syndrome caused by germline mutations in four DNA mismatch repair (MMR) genes: MSH2, MLH1, MSH6 and PMS2. Identifying the genetic basis of the disease has permitted the accurate identification of Lynch syndrome patients, but many who are suspected of suffering from a MMR deficiency based on family history or early onset of cancer plus family history lack detectable MMR gene point mutations in the genes involved.
In their study, Gylling et al. asked whether large genomic rearrangements and epigenetic changes could explain the observed cancer susceptibility in patients in whom clinical and immunohistochemical findings gave reason to suspect Lynch syndrome despite the absence of gene point mutations in MSH2, MLH1 and MSH6. Using multiplex ligation-dependent probe amplification (MPLA) and methylation-specific (MS)-MPLA the authors detected large genomic deletions in 12 out of 45 tested subjects and epigenetic germline mutations in MLH1 accompanied by monoallelic loss of RNA expression in two cases. In contrast to genomic rearrangements, which were associated with strong family histories for Lynch syndrome, epimutations occurred in patients with multiple early-onset tumors without any significant family history.
Together, genomic deletions and epigenetic changes explain a large fraction of point-mutation-negative families suspected of Lynch syndrome, giving clinicians an additional tool to clearly identify an inherited cancer predisposition. This allows for the close clinical surveillance of patients to catch tumors early on when the chance of treating them successfully remains high.
Sendai Virus Particles: A Weapon of Last Resort
Kawaguchi et al., pp 2478–2487
Virtually all prostate cancers are androgen-dependent at first and respond well to hormone deprivation. But in most cases, a small percentage of the tumor cells eventually become resistant, resulting in a significant drop in prognosis and a drastic narrowing of therapeutic choices. Looking for new treatment options, Kawaguchi et al. turned to Sendai virus, a paramyxovirus known for its robust fusion activity and the ability to induce type I interferon (IFN).
When the authors treated hormone-resistant human prostate cancer cell lines PC-3 and DU145 with various amounts of inactivated Sendai virus particles (specifically HVJ-E, short for hemagglutinating virus of Japan envelope) the viability of both cell lines dropped significantly, while hormone-sensitive LNCap cells and normal prostate epithelium (PNT2) were largely unaffected. Closer inspection revealed that HVJ-E preferentially bound to PC-3 and DU145 cells, in which it induced cell fusion and apoptosis via IFN secretion from tumor cells. When directly administered into PC3 tumor xenografts, HVJ-E completely eradicated the tumor mass after only 3 injections, apparently through a combination of cell fusion, secretion of IFN and enhanced activation of natural killer cells.
HVJ-E was originally developed as a drug delivery vector and efficiently drops off DNA, siRNA, proteins and chemotherapeutic drugs in cancer cells. Enhancing its natural ability to eradicate hormone-resistant prostate cancer with a freight of therapeutic molecules makes HVJ-E a promising candidate for androgen-independent prostate tumors.