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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 DMBA/TPA carcinogenic applications on Spalax and mice skin. Macroscopic and microscopic skin changes in Spalax(A) and mice (B). (A) Normal tissues (left images). Necrosis of skin and subcutaneous adipose tissue (middle images). Completely healed skin lesion showing epidermal thickening with hyperkeratosis and dermal fibrosis (right images). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). (B) Normal tissues (left images). Intra-epidermal blisters, partially ruptured with erosion formation and crusting, congestion and inflammatory cell infiltrate within the dermis indicate ongoing inflammation (middle images). Skin papillary outgrowths with thickened, dysplastic epidermis, numerous mitoses and foci are suggestive of squamous cell carcinoma (right image). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). DMBA/TPA, 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate.
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Figure 1: Effect of DMBA/TPA carcinogenic applications on Spalax and mice skin. Macroscopic and microscopic skin changes in Spalax(A) and mice (B). (A) Normal tissues (left images). Necrosis of skin and subcutaneous adipose tissue (middle images). Completely healed skin lesion showing epidermal thickening with hyperkeratosis and dermal fibrosis (right images). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). (B) Normal tissues (left images). Intra-epidermal blisters, partially ruptured with erosion formation and crusting, congestion and inflammatory cell infiltrate within the dermis indicate ongoing inflammation (middle images). Skin papillary outgrowths with thickened, dysplastic epidermis, numerous mitoses and foci are suggestive of squamous cell carcinoma (right image). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). DMBA/TPA, 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate.

Mentions: Spalax and C57BL/6 mice were treated with DMBA/TPA to induce skin cancer [19]. Spalax animals developed skin lesions within 10 days (Figure 1A, upper middle panel). Histological examination of hematoxylin and eosin-stained tissue sections demonstrated skin necrosis involving the deep parts of the dermis, massive infiltration of the affected areas with neutrophil leukocytes, and ulcerated epidermis focally covered with fibrino-purulent exudates (Figure 1A, lower middle panel). The subcutaneous skeletal muscle and bone tissues were not affected, and no tumor was identified. The wounds completely healed within seven to nine weeks, resulting in epidermal thickening (Figure 1A, right panels), and no further progression to skin tumors was observed, even though TPA treatments were extended to six months (November 2010 to April 2011). In the control group, Spalax animals treated with acetone only did not show any changes in their skin macro- and microstructure, similar to non-treated animals (Figure 1A, left panels). Following 7 to 10 days of DMBA/TPA treatment, mice demonstrated small intra-epidermal blisters; some of them ruptured, forming superficial erosions with extensive crusting (Figure 1B, middle panels), which subsequently underwent transformation into multiple skin tumors within two to three months (Figure 1B, upper right panel). Histological examination revealed papillary and flat epidermal outgrowths with dysplastic features, focally similar to squamous cell carcinoma (Figure 1B, right panels).


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 DMBA/TPA carcinogenic applications on Spalax and mice skin. Macroscopic and microscopic skin changes in Spalax(A) and mice (B). (A) Normal tissues (left images). Necrosis of skin and subcutaneous adipose tissue (middle images). Completely healed skin lesion showing epidermal thickening with hyperkeratosis and dermal fibrosis (right images). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). (B) Normal tissues (left images). Intra-epidermal blisters, partially ruptured with erosion formation and crusting, congestion and inflammatory cell infiltrate within the dermis indicate ongoing inflammation (middle images). Skin papillary outgrowths with thickened, dysplastic epidermis, numerous mitoses and foci are suggestive of squamous cell carcinoma (right image). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). DMBA/TPA, 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 1: Effect of DMBA/TPA carcinogenic applications on Spalax and mice skin. Macroscopic and microscopic skin changes in Spalax(A) and mice (B). (A) Normal tissues (left images). Necrosis of skin and subcutaneous adipose tissue (middle images). Completely healed skin lesion showing epidermal thickening with hyperkeratosis and dermal fibrosis (right images). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). (B) Normal tissues (left images). Intra-epidermal blisters, partially ruptured with erosion formation and crusting, congestion and inflammatory cell infiltrate within the dermis indicate ongoing inflammation (middle images). Skin papillary outgrowths with thickened, dysplastic epidermis, numerous mitoses and foci are suggestive of squamous cell carcinoma (right image). Hematoxylin and eosin staining, ×40 (left and middle images) and ×100 (right image). DMBA/TPA, 7,12-Dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate.
Mentions: Spalax and C57BL/6 mice were treated with DMBA/TPA to induce skin cancer [19]. Spalax animals developed skin lesions within 10 days (Figure 1A, upper middle panel). Histological examination of hematoxylin and eosin-stained tissue sections demonstrated skin necrosis involving the deep parts of the dermis, massive infiltration of the affected areas with neutrophil leukocytes, and ulcerated epidermis focally covered with fibrino-purulent exudates (Figure 1A, lower middle panel). The subcutaneous skeletal muscle and bone tissues were not affected, and no tumor was identified. The wounds completely healed within seven to nine weeks, resulting in epidermal thickening (Figure 1A, right panels), and no further progression to skin tumors was observed, even though TPA treatments were extended to six months (November 2010 to April 2011). In the control group, Spalax animals treated with acetone only did not show any changes in their skin macro- and microstructure, similar to non-treated animals (Figure 1A, left panels). Following 7 to 10 days of DMBA/TPA treatment, mice demonstrated small intra-epidermal blisters; some of them ruptured, forming superficial erosions with extensive crusting (Figure 1B, middle panels), which subsequently underwent transformation into multiple skin tumors within two to three months (Figure 1B, upper right panel). Histological examination revealed papillary and flat epidermal outgrowths with dysplastic features, focally similar to squamous cell carcinoma (Figure 1B, right panels).

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