Concise Review: Transmissible Animal Tumors as Models of the Cancer Stem-Cell Process

Abstract

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.

Transmissible cancers in an evolutionary context

“…Although the cancer progenitor cells are thought to be different according to the two theories, that is, somatic cells and CSCs, respectively, both theories portray cancer progression as the accumulation of genetic modifications (mutations and epigenetic alterations) and selection for, and subsequent expansion of, clones with highest survival and reproductive (proliferative) advantage. Interestingly, although transmissible animal cancers have been proposed to provide excellent model systems of the CSC process , a preliminary study focusing on the expression profiles of embryonic stem cell and pluripotent germ cell specific genes could not confirm the existence of CSCs in devil facial tumours . However, to univocally confirm or exclude the role of CSCs in transmissible cancer progression, additional experiments must be conducted, including identification of (i) a population of potential CSCs from fresh tumour samples and/or primary cell cultures and (ii) sarcosphere formation and self‐renewal assays, followed by gene signature analyses of stem cell markers, and (iii) once a possible stem cell population has been identified, the evaluation of number of cells required from the enriched CSCs and from primary cancers to initiate a tumour when xenotransplanted into immuno‐compromised mice would be the ultimate proof of CSC existence .…”

“…lysozyme‐40, vimentin, desmin, nestin, etc. ) have revealed that despite the clonal nature of vertebrate transmissible cancers, there is significant heterogeneity of lineage marker expression both within the tumour cell population and between individual tumours (reviewed by O'Neill ). The observed high intra‐tumour and inter‐tumour phenotypic heterogeneity on stable genomic backgrounds demonstrates that tumour cells engage in an incessant crosstalk between each other and their micro‐environment and phenotypically adjust to the changes of the surrounding stroma.…”

Molecular and Cellular Features of Murine Craniofacial and Trunk Neural Crest Cells as Stem Cell-Like Cells

“…Another example of a cancer thought to be NC-origin is Ewing sarcoma, an aggressive bone and soft tissue tumors [6] . Considering a recent idea of cancer stem cells [7] , [8] , NCCs may share molecular features common to malignant tumors.…”

A 41-gene signature derived from breast cancer stem cells as a predictor of survival

“…Since BCSCs are considered to be the root of metastasis, promote recurrence of the malignancy, and are resistant to traditional therapy [24-27], we tested this profile in a series of 198 consecutive patients who were diagnosed with early breast cancer. The results showed that the 41-gene profile performed best as a predictor of DMFS by classifying patients into high-EL and low-EL groups.…”