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Evidence is accumulating that tumour development is driven by cancer stem cells (CSCs). In order to understand the presence and potential contribution of stem cells (SCs) as tumour-initiating cells in canine cutaneous tumours, we selected three putative SC markers (Lgr5, Lgr6 and Sox9) and investigated their expression pattern, level of protein and mRNA expression, in 43 canine hair follicle (HF) and 18 canine cutaneous epidermal tumours by immunohistochemistry and qRT-PCR, using normal skin samples as controls. Lgr5 protein expression was not detected in epidermal and HF tumours; however, Lgr5 mRNA overexpression was evident in some HF tumours. Sox9 was expressed in several tumour cases, both at the protein and mRNA level. The Lgr6 antibody tested was not suitable for formalin-fixed paraffin-embedded tissue samples, but Lgr6 gene showed higher expression in several samples of both HF and epidermal tumours compared with normal skin. Significantly higher mRNA expression levels of the three SC markers were found in trichoblastomas (TB) compared with basal cell carcinomas (BCC). The present results indicated that canine HF and epidermal tumours might have common tumour-initiating cells. The mRNA expression of the three selected SC markers, especially Lgr5, could be potentially useful in the distinction between canine TB and BCC. [ABSTRACT FROM AUTHOR]

Non-adherent, 3-dimensional sphere formation is used as an in vitro surrogate to evaluate cellular potential for tumour initiation and self-renewal. To determine if a shared molecular program underlies the capacity for sphere formation by cells originating from diverse tumour types, we characterized molecular and functional properties of 10 independent cell lines derived from 3 ontogenetically distinct dog cancers: hemangiosarcoma, osteosarcoma and glial brain tumours. Genome-wide gene expression profiling identified tumour-of-origin-dependent patterns of adjustment to sphere formation in a uniform culture condition. However, expression of the stem/progenitor markers CD34 and CD117, resistance to cytotoxic drugs and dye efflux (side population assays) showed no association with these gene expression profiles. Instead, primary sphere-forming capacity was inversely correlated with the ability to reform secondary spheres, regardless of tumour ontogeny. Primary sphere formation seemed to be proportional to the number of pre-existing cells with sphere-forming capacity in the cell lines. Cell lines where secondary sphere formation was more proficient than primary sphere formation showed enrichment of genes involved in fatty acid synthesis and immunosuppressive cytokines. In contrast, cell lines where secondary sphere formation was approximately equivalent to or less proficient than primary sphere formation showed upregulation of CD40 and enrichment of genes involved in fatty acid oxidation. Our data suggest that in vitro sphere formation is associated with upregulation of gene clusters involved in metabolic and immunosuppressive functions, which might be necessary for self-renewal and for tumour initiation and/or tumour propagation in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Precursors of the hormone gastrin, progastrin and glycine-extended gastrin (G-gly), have been detected in colorectal polyps and tumours, and in the blood of patients with colorectal cancer (CRC), while their expression is lower in healthy subjects. The surface glycoproteins CD133 and CD44 have been identified as possible markers for CRC stem cells. Our aims were to investigate whether progastrin and G-gly are expressed by CD133-positive cells in human CRC tissues and in the human CRC cell line DLD-1, and to determine whether this expression is biologically relevant. The great majority of the cells expressing CD133 also expressed gastrin precursors in both DLD-1 cells, which retain a stem cell-like subpopulation, and human CRC specimens. The CD133high/CD44high/progastrinhigh cells gave rise to larger tumours in SCID mice compared to CD133low/CD44low/progastrinlow cells. The CD133high/CD44high/progastrinhigh cells displayed enhanced activation of the signalling molecules JAK2, STAT3, ERK1/2 and Akt, known to regulate the induction of proliferation and/or survival by gastrin precursors. Moreover, downregulation of the gastrin gene in DLD-1 cells reduced the expression of cancer stem cell markers and abolished tumour development in SCID mice. We conclude that gastrin precursors may provide a target for therapies directed against the cells responsible for tumour development and recurrence. [Copyright &y& Elsevier]