Concise review: transmissible animal tumors as models of the cancer stem-cell process.

Tasmanian devil facial tumor disease (DFTD) and canine transmissible venereal tumor (CTVT) are highly unusual cancers capable of being transmitted between animals as an allograft. The concept that these tumors represent a cancer stem-cell process has never been formally evaluated. For each, evidence of self-renewal is found in the natural history of these tumors in the wild, tumor initiation in recipient animals, and serial transplantation studies. Additional data for stem-cell-specific genes and markers in DFTD also exist. Although both tumor types manifest as undifferentiated cancers, immunocytohistochemistry supports a histiocytic phenotype for CTVT and a neural crest origin, possibly a Schwann-cell phenotype, for DFTD. In these data, differential expression of lineage markers is seen which may suggest some capacity for differentiation toward a heterogeneous variety of cell types. It is proposed that DFTD and CTVT may represent and may serve as models of the cancer stem-cell process, but formal investigation is required to clarify this. Appreciation of any such role may act as a stimulus to ongoing research in the pathology of DFTD and CTVT, including further characterization of their origin and phenotype and possible therapeutic approaches. Additionally, they may provide valuable models for future studies of their analogous human cancers, including any putative CSC component.

Homozygosity for constitutional chromosomal rearrangements: a systematic review with reference to origin, ascertainment and phenotype.

Chromosomal translocations and inversions are present in ∼0.6-1% of individuals. Although the majority are inherited, and the familial transmission across generations is well reported, reports of homozygosity are relatively rare, with most data in the form of individual case reports. A systematic review of all published cases was performed with particular attention to origin, ascertainment and phenotype of the reported homozygosity. A total of 10 cases of Robertsonian translocation (RBT), 6 reciprocal translocation and 19 cases of inversion homozygosity were identified. In RBT homozygosity, the majority of individuals are phenotypically normal, arise from inbreeding within a family that carries a familial translocation, and are ascertained following identification of an existing familial rearrangement rather than any feature specific to the homozygosity. In addition, they are fertile and as expected, their offspring are heterozygous for the translocation. For reciprocal translocations, homozygosity arises in individuals born to related parents from a family who harbor a unique familial translocation. Ascertainment is following investigation of phenotypic abnormalities resulting from consanguinity per se and/or the unmasking of a specific gene mutation. For chromosomal inversions, homozygosity may originate from either related or non-consanguinous parentage. Although many cases are ascertained because of an associated phenotypic abnormality, a high proportion of cases are of normal phenotype and a direct causal relationship is uncertain. There are fewer reports of both Robertsonian and inversion homozygosity than may be expected from the relative frequencies of each class within the population.

Tasmanian devil facial tumor disease: insights into reduced tumor surveillance from an unusual malignancy.

Tasmanian devil facial tumor disease (DFTD) is a highly aggressive cancer involving the facial tissues that currently presents a serious extinction risk for the Tasmanian devil population. Although the histogenesis is uncertain, an origin from a neural crest cell-lineage is considered likely. Epidemiological, cytogenetic and immunological data all support the premise that DFTD arose from a single tumor clone from an individual diseased animal, and is being transmitted between individual animals as a tumor "allograft" by biting during social interaction. The spread of this cancer throughout the species is believed to be facilitated by a reduced MHC diversity, possibly as a result of an evolutionary bottleneck. The pathogenesis of DFTD has some similarities with certain human cancers, including donor-recipient tumor transmission, which may complicate organ transplantation, and certain forms of malignancy at the maternal/fetal interface. The natural history and pathology of DFTD, and the data describing this highly unusual tumor biology are discussed.

Gefitinib as targeted therapy for mucoepidermoid carcinoma of the lung: possible significance of CRTC1-MAML2 oncogene.

Recent reports of a clinical response to gefitinib in pulmonary mucoepidermoid carcinoma (MEC) in the absence of sensitizing EGFR mutations suggest that tyrosine kinase inhibitors (TKIs) may be effective in this tumor type. Although not documented in these reports, MEC of the lung may harbor a t(11;19) translocation with an associated novel fusion oncogene (CRTC1-MAML2). Furthermore, MECs arising in the salivary glands carry this mutation in a high proportion of cases. In vitro data has shown that MEC cell-lines with t(11;19) are sensitive to gefitinib and that this may be mediated by the action of CRTC1-MAML2 in up-regulating the EGFR ligand, amphiregulin. Data also shows that gefitinib demonstrates amphiregulin-dependant activity in NSCLC cell-lines. As such, it may be speculated that MEC from lung and salivary glands expressing CRTC1-MAML2 present a valid target for treatment with gefitinib, even in the absence of sensitizing EGFR mutations. Clinical studies are required to test this hypothesis.

t(11;19) translocation and CRTC1-MAML2 fusion oncogene in mucoepidermoid carcinoma.

Mucoepidermoid carcinoma (MEC) is a relatively uncommon carcinoma of variable histology that can involve many tissue types, most commonly major and minor salivary glands and the tracheo-bronchial tree. In a significant number of cases a recurring t(11;19) translocation with an associated novel fusion oncogene (CRTC1-MAML2) is present. This translocation is also found in Warthin's tumour and clear cell hidradenoma of the skin. The CRTC1-MAML2 oncogene acts as a transcription factor on Notch and CREB regulatory pathways, disrupting normal cell-cycle and differentiation, contributing to tumour development. Data suggest that in MEC, the presence of CRTC1-MAML2 may have some prognostic value. An understanding of these mechanisms extends our knowledge of the role of fusion oncogenes in epithelial malignancy. A review of CRTC1-MAML2 in MEC is presented.