Limits...
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.

Show MeSH

Related in: MedlinePlus

3MCA-induced tumor in Spalax. (A) Light microscopic examination. Note spindle, epithelioid and giant multinuclear cells (empty arrow); nuclei are variable in shape, size and chromatin distribution; nucleoli vary in frequency. Hematoxylin and eosin staining, ×100. (B) Transmission electron microscopy (TEM): dilated, elongated rough endoplasmic reticulum (black arrows) and abundant collagen fibers (white arrows) (C) TEM: a giant, monstrous nucleus (N). (D) Cell line established from Spalax tumor, phase contrast image after six months of continuous cultivation (×200). 3MCA, 3-Methylcholantrene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3750378&req=5

Figure 3: 3MCA-induced tumor in Spalax. (A) Light microscopic examination. Note spindle, epithelioid and giant multinuclear cells (empty arrow); nuclei are variable in shape, size and chromatin distribution; nucleoli vary in frequency. Hematoxylin and eosin staining, ×100. (B) Transmission electron microscopy (TEM): dilated, elongated rough endoplasmic reticulum (black arrows) and abundant collagen fibers (white arrows) (C) TEM: a giant, monstrous nucleus (N). (D) Cell line established from Spalax tumor, phase contrast image after six months of continuous cultivation (×200). 3MCA, 3-Methylcholantrene.

Mentions: A single, old Spalax individual developed a 3-MCA-induced tumor 18 months after initial treatment (Figure 3). A biopsy was performed, and the histological examination revealed a partially necrotic and heavily inflamed, spindle and epithelioid cell tumor with infiltrative borders and myxoid stroma. Cells demonstrated dyscohesion, polymorphism in size and shape (bizarre and giant cells present) and prominent nuclear atypia (Figure 3A). This hypercellular tumor demonstrated high mitotic activity (above 30 mitoses per 10 high power fields) with abundant atypical mitotic figures. Transmission electron microscopy revealed fibrosarcoma-like findings [21]: deformed nuclei, some with monstrous appearance; long branching and dilated rough endoplasmic reticulum and abundance of extracellular collagen fibers (Figure 3B,C). Myofibroblastic differentiation features were not observed. An immortal cell line was established from the tumor sample. The cultured adherent cells show a typical fibroblast phenotype (Figure 3D), which has remained unchanged throughout a long culture time (40 passages, 8 months after isolation).


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)

3MCA-induced tumor in Spalax. (A) Light microscopic examination. Note spindle, epithelioid and giant multinuclear cells (empty arrow); nuclei are variable in shape, size and chromatin distribution; nucleoli vary in frequency. Hematoxylin and eosin staining, ×100. (B) Transmission electron microscopy (TEM): dilated, elongated rough endoplasmic reticulum (black arrows) and abundant collagen fibers (white arrows) (C) TEM: a giant, monstrous nucleus (N). (D) Cell line established from Spalax tumor, phase contrast image after six months of continuous cultivation (×200). 3MCA, 3-Methylcholantrene.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: 3MCA-induced tumor in Spalax. (A) Light microscopic examination. Note spindle, epithelioid and giant multinuclear cells (empty arrow); nuclei are variable in shape, size and chromatin distribution; nucleoli vary in frequency. Hematoxylin and eosin staining, ×100. (B) Transmission electron microscopy (TEM): dilated, elongated rough endoplasmic reticulum (black arrows) and abundant collagen fibers (white arrows) (C) TEM: a giant, monstrous nucleus (N). (D) Cell line established from Spalax tumor, phase contrast image after six months of continuous cultivation (×200). 3MCA, 3-Methylcholantrene.
Mentions: A single, old Spalax individual developed a 3-MCA-induced tumor 18 months after initial treatment (Figure 3). A biopsy was performed, and the histological examination revealed a partially necrotic and heavily inflamed, spindle and epithelioid cell tumor with infiltrative borders and myxoid stroma. Cells demonstrated dyscohesion, polymorphism in size and shape (bizarre and giant cells present) and prominent nuclear atypia (Figure 3A). This hypercellular tumor demonstrated high mitotic activity (above 30 mitoses per 10 high power fields) with abundant atypical mitotic figures. Transmission electron microscopy revealed fibrosarcoma-like findings [21]: deformed nuclei, some with monstrous appearance; long branching and dilated rough endoplasmic reticulum and abundance of extracellular collagen fibers (Figure 3B,C). Myofibroblastic differentiation features were not observed. An immortal cell line was established from the tumor sample. The cultured adherent cells show a typical fibroblast phenotype (Figure 3D), which has remained unchanged throughout a long culture time (40 passages, 8 months after isolation).

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