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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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Effects of Spalax and mouse fibroblasts on growth of co-cultured human hepatoma cells. Tumor cells (TC) were cultured either alone or in the presence of Spalax or mouse fibroblasts in the ratio of 1:10 (5 × 104 fibroblasts and 5 × 103 cancer cells in six-well plates) in RPMI/DMEM-F12 media (1:1) containing 10% FBS. White arrows point to the foci of destroyed cancer cells, and black arrows show the fibroblast-tumor cell colony boundaries. Cells in mono- and co-cultures were observed and photographed daily. Representative images for each sample at different time intervals are shown (×200).
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Figure 4: Effects of Spalax and mouse fibroblasts on growth of co-cultured human hepatoma cells. Tumor cells (TC) were cultured either alone or in the presence of Spalax or mouse fibroblasts in the ratio of 1:10 (5 × 104 fibroblasts and 5 × 103 cancer cells in six-well plates) in RPMI/DMEM-F12 media (1:1) containing 10% FBS. White arrows point to the foci of destroyed cancer cells, and black arrows show the fibroblast-tumor cell colony boundaries. Cells in mono- and co-cultures were observed and photographed daily. Representative images for each sample at different time intervals are shown (×200).

Mentions: To compare the effects of normal fibroblasts isolated from different rodents on the growth of human cancer cells, we used a co-culture approach, where fibroblasts were cultured together with cancer cells on a shared surface (Figures 4 and 5). In these experiments, hepatoma-derived Hep3B cells as well as breast cancer MCF7 cells were tested. Obvious inhibition of cancer cell growth was found when Hep3B cells were co-cultured with Spalax normal lung and skin fibroblasts: the foci of destroyed cancer cells were visible after six days of co-culture (Figure 4). Prolonged co-cultivation up to 11 days resulted in further destruction of cancer cell colonies by the presence of Spalax fibroblasts and the spaces previously occupied by Hep3B cells were invaded by fibroblasts (Figure 4). In contrast, the number of cancer cells co-cultured with mouse fibroblasts increased gradually, and on Day 6, Hep3B cells surrounded by mouse fibroblasts reached approximately 80% confluence, similar to control (Hep3B only). Overgrown Hep3B colonies were found after 11-day co-culture with mouse fibroblasts. An obvious inhibitory effect was demonstrated when Spalax normal skin fibroblasts were co-cultured with breast cancer MCF7 cells as well (Figure 5). After 10 days of co-culture with Spalax fibroblasts, massive rounding and detachment of cancer cells were observed. On the other hand, mouse fibroblasts stimulated proliferation of MCF7 cells, and by Day 10 densely populated colonies of cancer cells developed.


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)

Effects of Spalax and mouse fibroblasts on growth of co-cultured human hepatoma cells. Tumor cells (TC) were cultured either alone or in the presence of Spalax or mouse fibroblasts in the ratio of 1:10 (5 × 104 fibroblasts and 5 × 103 cancer cells in six-well plates) in RPMI/DMEM-F12 media (1:1) containing 10% FBS. White arrows point to the foci of destroyed cancer cells, and black arrows show the fibroblast-tumor cell colony boundaries. Cells in mono- and co-cultures were observed and photographed daily. Representative images for each sample at different time intervals are shown (×200).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Effects of Spalax and mouse fibroblasts on growth of co-cultured human hepatoma cells. Tumor cells (TC) were cultured either alone or in the presence of Spalax or mouse fibroblasts in the ratio of 1:10 (5 × 104 fibroblasts and 5 × 103 cancer cells in six-well plates) in RPMI/DMEM-F12 media (1:1) containing 10% FBS. White arrows point to the foci of destroyed cancer cells, and black arrows show the fibroblast-tumor cell colony boundaries. Cells in mono- and co-cultures were observed and photographed daily. Representative images for each sample at different time intervals are shown (×200).
Mentions: To compare the effects of normal fibroblasts isolated from different rodents on the growth of human cancer cells, we used a co-culture approach, where fibroblasts were cultured together with cancer cells on a shared surface (Figures 4 and 5). In these experiments, hepatoma-derived Hep3B cells as well as breast cancer MCF7 cells were tested. Obvious inhibition of cancer cell growth was found when Hep3B cells were co-cultured with Spalax normal lung and skin fibroblasts: the foci of destroyed cancer cells were visible after six days of co-culture (Figure 4). Prolonged co-cultivation up to 11 days resulted in further destruction of cancer cell colonies by the presence of Spalax fibroblasts and the spaces previously occupied by Hep3B cells were invaded by fibroblasts (Figure 4). In contrast, the number of cancer cells co-cultured with mouse fibroblasts increased gradually, and on Day 6, Hep3B cells surrounded by mouse fibroblasts reached approximately 80% confluence, similar to control (Hep3B only). Overgrown Hep3B colonies were found after 11-day co-culture with mouse fibroblasts. An obvious inhibitory effect was demonstrated when Spalax normal skin fibroblasts were co-cultured with breast cancer MCF7 cells as well (Figure 5). After 10 days of co-culture with Spalax fibroblasts, massive rounding and detachment of cancer cells were observed. On the other hand, mouse fibroblasts stimulated proliferation of MCF7 cells, and by Day 10 densely populated colonies of cancer cells developed.

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