Abstract
The self-renewal potential of a cancer cell can be estimated by using particular assays, which include xenotransplantation in immunocompromised animals or culturing in non-adherent serum-free stem-cells media (SCM). However, whether cells with self-renewal potential actually contribute to disease is unknown. Here we investigated the tumorigenic potential and fate of cancer cells in an in-vivo melanoma model. We examined cell lines which were derived from the same parental line: a non-metastatic cell line (K1735/16), a metastatic cell line (K1735/M4) and a cell line which was selected in non-adherent conditions (K1735/16S). All cell lines exhibited similar proliferation kinetics when grown on culture plates. K1735/16 cells grown in soft agar or in suspension non-adherent conditions failed to form colonies or spheroids, whereas the other cell lines showed prominent colonogenicity and spheroid formation capacity. By using sphere limiting dilution analysis (SLDA) in serum-free media, K1735/16S and K1735/M4 cells grown in suspension were capable of forming spheroids even in low frequencies of concentrations, as opposed to K1735/16 cells. The tumorigenic potential of the cell lines was determined in SCID mice using intra footpad injections. Palpable tumors were evident in all mice. In agreement with the in-vitro studies, the K1735/M4 cell line exhibited the highest growth kinetics, followed by the K1735/16S cell line, whereas the K1735/16 cell line had the lowest tumor growth potential (P<0.001). In contrast, when we repeated the experiments in syngeneic C3H/HeN mice, the K1735/16 cell line produced macroscopic tumors 30–100 days after injection, whereas K1735/M4 and K1735/16S derived tumors regressed spontaneously in 90–100% of mice. TUNEL analysis revealed significantly higher number of apoptotic cells in K1735/16S and K1735/M4 cell line-derived tumors compared to K1735/16 tumors (P<0.001). The models we have examined here raised the possibility, that cells with high-tumorigenic activity may be more immunogenic and hence are more susceptible to immune-regulation.
Highlights
Cancer is a complex disease, involving differences between tumors or cells within a given tumor, as well as variation between patients
In order to assess the correlation between cancer cell selfrenewal potential and cell fate, we selected murine melanoma cells, which were derived from the same parental cell line, but which have different phenotypes in-vivo and in-vitro
The K1735/16 is a non-metastatic cell line and the K1735/M4 cell line was derived from a lung metastasis and has a high metastatic potential
Summary
Cancer is a complex disease, involving differences between tumors or cells within a given tumor, as well as variation between patients. Within the spectrum of cells in a given tumor, subpopulations of cells may be phenotypically different and exhibit distinct proliferative potential. The cancer stem cell (CSC) model suggests that only a small subpopulation of cells has a self-renewal and tumor formation potential, while the majority of the tumor consists of non-tumorigenic cells [1]. The only assay that determines the tumorigenic potential of human tumors involves xenotransplantation of different subpopulations of cancer cells into flanks of highly immunosuppressive animals (e.g. NOD/SCID mice). It has been demonstrated that the sphereforming potential in suspension non-adherent conditions consistently correlates with the neoplastic growth potential in immunosuppressed mice [17,18,19,20]
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