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Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitro evidence.

Manov I, Hirsh M, Iancu TC, Malik A, Sotnichenko N, Band M, Avivi A, Shams I - BMC Biol. (2013)

Bottom Line: This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation.Spalax fibroblast conditioned media had no effect on proliferation of noncancerous cells.Obviously, along with adaptation to hypoxia, Spalax has evolved efficient anti-cancer mechanisms yet to be elucidated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Evolution, University of Haifa, Haifa 31095, Israel.

ABSTRACT

Background: Subterranean blind mole rats (Spalax) are hypoxia tolerant (down to 3% O2), long lived (>20 years) rodents showing no clear signs of aging or aging related disorders. In 50 years of Spalax research, spontaneous tumors have never been recorded among thousands of individuals. Here we addressed the questions of (1) whether Spalax is resistant to chemically-induced tumorigenesis, and (2) whether normal fibroblasts isolated from Spalax possess tumor-suppressive activity.

Results: Treating animals with 3-Methylcholantrene (3MCA) and 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA), two potent carcinogens, confirmed Spalax high resistance to chemically induced cancers. While all mice and rats developed the expected tumors following treatment with both carcinogens, among Spalax no tumors were observed after DMBA/TPA treatment, while 3MCA induced benign fibroblastic proliferation in 2 Spalax individuals out of12, and only a single animal from the advanced age group developed malignancy 18 months post-treatment. The remaining animals are still healthy 30 months post-treatment. In vitro experiments showed an extraordinary ability of normal Spalax cultured fibroblasts to restrict malignant behavior in a broad spectrum of human-derived and in newly isolated Spalax 3MCA-induced cancer cell lines. Growth of cancer cells was inhibited by either direct interaction with Spalax fibroblasts or with soluble factors released into culture media and soft agar. This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation. Cells from another cancer resistant subterranean mammal, the naked mole rat, were also tested for direct effect on cancer cells and, similar to Spalax, demonstrated anti-cancer activity. No effect on cancer cells was observed using fibroblasts from mouse, rat or Acomys. Spalax fibroblast conditioned media had no effect on proliferation of noncancerous cells.

Conclusions: This report provides pioneering evidence that Spalax is not only resistant to spontaneous cancer but also to experimentally induced cancer, and shows the unique ability of Spalax normal fibroblasts to inhibit growth and kill cancer cells, but not normal cells, either through direct fibroblast-cancer cell interaction or via soluble factors. Obviously, along with adaptation to hypoxia, Spalax has evolved efficient anti-cancer mechanisms yet to be elucidated. Exploring the molecular mechanisms allowing Spalax to survive in extreme environments and to escape cancer as well as to kill homologous and heterologous cancer cells may hold the key for understanding the molecular nature of host resistance to cancer and identify new anti-cancer strategies for treating humans.

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Effect of Spalax, rat and mouse fibroblasts on Spalax-derived fibrosarcoma cells colony formation. (A) SpFS2240 Cancer cells were grown in soft agar on top of monolayers of mouse, rat and Spalax fibroblasts. After three weeks, colonies were counted. At least 10 fields were recorded for each observation. Two representative images demonstrating effects of different fibroblasts on colony-formation are shown (×40). (B) Colony numbers and cumulative total colony area (μm2) from five fields were calculated to demonstrate the effects of the fibroblasts monolayer on the cancer cell colony formation and growth.
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Figure 11: Effect of Spalax, rat and mouse fibroblasts on Spalax-derived fibrosarcoma cells colony formation. (A) SpFS2240 Cancer cells were grown in soft agar on top of monolayers of mouse, rat and Spalax fibroblasts. After three weeks, colonies were counted. At least 10 fields were recorded for each observation. Two representative images demonstrating effects of different fibroblasts on colony-formation are shown (×40). (B) Colony numbers and cumulative total colony area (μm2) from five fields were calculated to demonstrate the effects of the fibroblasts monolayer on the cancer cell colony formation and growth.

Mentions: Importantly, Spalax normal fibroblasts suppressed growth and colony formation of the homologous tumor, Spalax-derived fibrosarcoma (SpFS2240) (Figure 11). In contrast, both rat and mouse normal fibroblasts stimulated growth of Spalax tumor cells in soft agar (Figure 11A). Integrating the number of colonies and their total occupied area, calculated from five independent fields, revealed a 36% reduction when SpFS2240 were grown above a Spalax fibroblast monolayer compared to blank plates (Figure 11B, 2240 alone). In contrast, mouse and rat fibroblasts enhanced colony formation by factors of 1.7 and 2.1, respectively, compared to the blank plates (Figure 11B).


Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitro evidence.

Manov I, Hirsh M, Iancu TC, Malik A, Sotnichenko N, Band M, Avivi A, Shams I - BMC Biol. (2013)

Effect of Spalax, rat and mouse fibroblasts on Spalax-derived fibrosarcoma cells colony formation. (A) SpFS2240 Cancer cells were grown in soft agar on top of monolayers of mouse, rat and Spalax fibroblasts. After three weeks, colonies were counted. At least 10 fields were recorded for each observation. Two representative images demonstrating effects of different fibroblasts on colony-formation are shown (×40). (B) Colony numbers and cumulative total colony area (μm2) from five fields were calculated to demonstrate the effects of the fibroblasts monolayer on the cancer cell colony formation and growth.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750378&req=5

Figure 11: Effect of Spalax, rat and mouse fibroblasts on Spalax-derived fibrosarcoma cells colony formation. (A) SpFS2240 Cancer cells were grown in soft agar on top of monolayers of mouse, rat and Spalax fibroblasts. After three weeks, colonies were counted. At least 10 fields were recorded for each observation. Two representative images demonstrating effects of different fibroblasts on colony-formation are shown (×40). (B) Colony numbers and cumulative total colony area (μm2) from five fields were calculated to demonstrate the effects of the fibroblasts monolayer on the cancer cell colony formation and growth.
Mentions: Importantly, Spalax normal fibroblasts suppressed growth and colony formation of the homologous tumor, Spalax-derived fibrosarcoma (SpFS2240) (Figure 11). In contrast, both rat and mouse normal fibroblasts stimulated growth of Spalax tumor cells in soft agar (Figure 11A). Integrating the number of colonies and their total occupied area, calculated from five independent fields, revealed a 36% reduction when SpFS2240 were grown above a Spalax fibroblast monolayer compared to blank plates (Figure 11B, 2240 alone). In contrast, mouse and rat fibroblasts enhanced colony formation by factors of 1.7 and 2.1, respectively, compared to the blank plates (Figure 11B).

Bottom Line: This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation.Spalax fibroblast conditioned media had no effect on proliferation of noncancerous cells.Obviously, along with adaptation to hypoxia, Spalax has evolved efficient anti-cancer mechanisms yet to be elucidated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Evolution, University of Haifa, Haifa 31095, Israel.

ABSTRACT

Background: Subterranean blind mole rats (Spalax) are hypoxia tolerant (down to 3% O2), long lived (>20 years) rodents showing no clear signs of aging or aging related disorders. In 50 years of Spalax research, spontaneous tumors have never been recorded among thousands of individuals. Here we addressed the questions of (1) whether Spalax is resistant to chemically-induced tumorigenesis, and (2) whether normal fibroblasts isolated from Spalax possess tumor-suppressive activity.

Results: Treating animals with 3-Methylcholantrene (3MCA) and 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA), two potent carcinogens, confirmed Spalax high resistance to chemically induced cancers. While all mice and rats developed the expected tumors following treatment with both carcinogens, among Spalax no tumors were observed after DMBA/TPA treatment, while 3MCA induced benign fibroblastic proliferation in 2 Spalax individuals out of12, and only a single animal from the advanced age group developed malignancy 18 months post-treatment. The remaining animals are still healthy 30 months post-treatment. In vitro experiments showed an extraordinary ability of normal Spalax cultured fibroblasts to restrict malignant behavior in a broad spectrum of human-derived and in newly isolated Spalax 3MCA-induced cancer cell lines. Growth of cancer cells was inhibited by either direct interaction with Spalax fibroblasts or with soluble factors released into culture media and soft agar. This was accompanied by decreased cancer cell viability, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation and mitochondrial fragmentation. Cells from another cancer resistant subterranean mammal, the naked mole rat, were also tested for direct effect on cancer cells and, similar to Spalax, demonstrated anti-cancer activity. No effect on cancer cells was observed using fibroblasts from mouse, rat or Acomys. Spalax fibroblast conditioned media had no effect on proliferation of noncancerous cells.

Conclusions: This report provides pioneering evidence that Spalax is not only resistant to spontaneous cancer but also to experimentally induced cancer, and shows the unique ability of Spalax normal fibroblasts to inhibit growth and kill cancer cells, but not normal cells, either through direct fibroblast-cancer cell interaction or via soluble factors. Obviously, along with adaptation to hypoxia, Spalax has evolved efficient anti-cancer mechanisms yet to be elucidated. Exploring the molecular mechanisms allowing Spalax to survive in extreme environments and to escape cancer as well as to kill homologous and heterologous cancer cells may hold the key for understanding the molecular nature of host resistance to cancer and identify new anti-cancer strategies for treating humans.

Show MeSH
Related in: MedlinePlus