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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 3-Methylcholantren treatment on soft tissue tumor induction in Spalax and mice. Animals treated with a single injection of 3MCA as described in the Materials and methods section. Representative images show macroscopic and microscopic observations. Mice (A): An ill-defined, soft mass, with foci of necrosis and hemorrhage; diagnosed as high-grade fibrosarcoma by histology. Spalax (B): a well-circumscribed, firm, whitish nodule composed of benign spindle cells organized into long regular bundles - benign reactive fibrosis. Hematoxylin and eosin staining, ×100. 3MCA, 3-Methylcholantrene.
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Figure 2: Effect of 3-Methylcholantren treatment on soft tissue tumor induction in Spalax and mice. Animals treated with a single injection of 3MCA as described in the Materials and methods section. Representative images show macroscopic and microscopic observations. Mice (A): An ill-defined, soft mass, with foci of necrosis and hemorrhage; diagnosed as high-grade fibrosarcoma by histology. Spalax (B): a well-circumscribed, firm, whitish nodule composed of benign spindle cells organized into long regular bundles - benign reactive fibrosis. Hematoxylin and eosin staining, ×100. 3MCA, 3-Methylcholantrene.

Mentions: The ability of a single subcutaneous 3-MCA injection to induce fibrosarcoma is well documented [20]. The expected tumors appeared within two to three months in mice, and in four to six months in rats. Hypercellular spindle cell tumors with highly pleiomorphic, extensively proliferating cells (30 and more mitotic figures per 10 high power fields) arranged into intersected bundles or wide sheets were identified. Scant, partially myxoid stroma and areas of hemorrhagic necrosis were typical findings (Figure 2A). All examined tumors developed in 3-MCA-treated mice and rats were histologically identified as fibrosarcomas. Importantly, Spalax did not show any pathological process for over a year. However, by 14 to 16 months following the 3-MCA treatment, 2 of the Spalax animals (out of 6 old individuals and a total of 12 animals) developed a tissue overgrowth at the site of the injection. These lesions were well circumscribed in shape, unlike the ill-defined tumors found in mice and rats (Figure 2B). Histological examination revealed benign spindle cell proliferation most probably reflecting fibrosis at the site of an incompletely resolved inflammatory reaction.


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 3-Methylcholantren treatment on soft tissue tumor induction in Spalax and mice. Animals treated with a single injection of 3MCA as described in the Materials and methods section. Representative images show macroscopic and microscopic observations. Mice (A): An ill-defined, soft mass, with foci of necrosis and hemorrhage; diagnosed as high-grade fibrosarcoma by histology. Spalax (B): a well-circumscribed, firm, whitish nodule composed of benign spindle cells organized into long regular bundles - benign reactive fibrosis. Hematoxylin and eosin staining, ×100. 3MCA, 3-Methylcholantrene.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Effect of 3-Methylcholantren treatment on soft tissue tumor induction in Spalax and mice. Animals treated with a single injection of 3MCA as described in the Materials and methods section. Representative images show macroscopic and microscopic observations. Mice (A): An ill-defined, soft mass, with foci of necrosis and hemorrhage; diagnosed as high-grade fibrosarcoma by histology. Spalax (B): a well-circumscribed, firm, whitish nodule composed of benign spindle cells organized into long regular bundles - benign reactive fibrosis. Hematoxylin and eosin staining, ×100. 3MCA, 3-Methylcholantrene.
Mentions: The ability of a single subcutaneous 3-MCA injection to induce fibrosarcoma is well documented [20]. The expected tumors appeared within two to three months in mice, and in four to six months in rats. Hypercellular spindle cell tumors with highly pleiomorphic, extensively proliferating cells (30 and more mitotic figures per 10 high power fields) arranged into intersected bundles or wide sheets were identified. Scant, partially myxoid stroma and areas of hemorrhagic necrosis were typical findings (Figure 2A). All examined tumors developed in 3-MCA-treated mice and rats were histologically identified as fibrosarcomas. Importantly, Spalax did not show any pathological process for over a year. However, by 14 to 16 months following the 3-MCA treatment, 2 of the Spalax animals (out of 6 old individuals and a total of 12 animals) developed a tissue overgrowth at the site of the injection. These lesions were well circumscribed in shape, unlike the ill-defined tumors found in mice and rats (Figure 2B). Histological examination revealed benign spindle cell proliferation most probably reflecting fibrosis at the site of an incompletely resolved inflammatory reaction.

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