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Canine Mammary Cancer Stem Cells are Radio- and Chemo- Resistant and Exhibit an Epithelial-Mesenchymal Transition Phenotype.

Pang LY, Cervantes-Arias A, Else RW, Argyle DJ - Cancers (Basel) (2011)

Bottom Line: Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs.Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype.Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

View Article: PubMed Central - PubMed

Affiliation: Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK. lisa.pang@ed.ac.uk.

ABSTRACT
Canine mammary carcinoma is the most common cancer among female dogs and is often fatal due to the development of distant metastases. In humans, solid tumors are made up of heterogeneous cell populations, which perform different roles in the tumor economy. A small subset of tumor cells can hold or acquire stem cell characteristics, enabling them to drive tumor growth, recurrence and metastasis. In veterinary medicine, the molecular drivers of canine mammary carcinoma are as yet undefined. Here we report that putative cancer stem cells (CSCs) can be isolated form a canine mammary carcinoma cell line, REM134. We show that these cells have an increased ability to form tumorspheres, a characteristic of stem cells, and that they express embryonic stem cell markers associated with pluripotency. Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs. The epithelial to mesenchymal transition (EMT) has been associated with cancer invasion, metastasis, and the acquisition of stem cell characteristics. Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype. Furthermore, we show that canine mammary cancer cells can be induced to undergo EMT by TGFβ and that these cells have an increased ability to form tumorspheres. Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

No MeSH data available.


Related in: MedlinePlus

Tumorspheres exhibit increased resistance to conventional chemo- and radiation therapies. Adherent cells and tumorspheres were treated with increasing concentrations of doxorubicin and cell viability was assayed 72 hours post-treatment (★ p = 0.008; ★ ★ p = 0.038; #p < 0.001) (A). Radiation sensitivity was determined by assaying for cell viability 72 hours post-treatment (★ p = 0.003; ★ ★ p = 0.026; ★ ★ ★ p = 0.002) (B) and by determining colony forming ability (★ p = 0.01; ★ ★ p = 0.009; ★ ★ ★ p < 0.001) (C).
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f2-cancers-03-01744: Tumorspheres exhibit increased resistance to conventional chemo- and radiation therapies. Adherent cells and tumorspheres were treated with increasing concentrations of doxorubicin and cell viability was assayed 72 hours post-treatment (★ p = 0.008; ★ ★ p = 0.038; #p < 0.001) (A). Radiation sensitivity was determined by assaying for cell viability 72 hours post-treatment (★ p = 0.003; ★ ★ p = 0.026; ★ ★ ★ p = 0.002) (B) and by determining colony forming ability (★ p = 0.01; ★ ★ p = 0.009; ★ ★ ★ p < 0.001) (C).

Mentions: To determine whether tumorspheres cells preferentially survive after treatment with chemotherapeutic agents, tumorspheres were dissociated into single cells and treated with increasing concentrations of the cancer chemotherapeutic drug, doxorubicin. Doxorubicin is an anti-tumor antibiotic DNA damaging agent and is commonly used in veterinary and human cancer chemotherapy protocols. We used doses of Doxorubicin in cell culture experiments that correlate to concentrations that can be achieved in vivo. Cell viability was assayed 72 hours after treatment. Cells from tumorspheres demonstrated a significantly increased resistance to the cytotoxic effect of doxorubicin compared to parental adherent cells (Figure 2A).


Canine Mammary Cancer Stem Cells are Radio- and Chemo- Resistant and Exhibit an Epithelial-Mesenchymal Transition Phenotype.

Pang LY, Cervantes-Arias A, Else RW, Argyle DJ - Cancers (Basel) (2011)

Tumorspheres exhibit increased resistance to conventional chemo- and radiation therapies. Adherent cells and tumorspheres were treated with increasing concentrations of doxorubicin and cell viability was assayed 72 hours post-treatment (★ p = 0.008; ★ ★ p = 0.038; #p < 0.001) (A). Radiation sensitivity was determined by assaying for cell viability 72 hours post-treatment (★ p = 0.003; ★ ★ p = 0.026; ★ ★ ★ p = 0.002) (B) and by determining colony forming ability (★ p = 0.01; ★ ★ p = 0.009; ★ ★ ★ p < 0.001) (C).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757388&req=5

f2-cancers-03-01744: Tumorspheres exhibit increased resistance to conventional chemo- and radiation therapies. Adherent cells and tumorspheres were treated with increasing concentrations of doxorubicin and cell viability was assayed 72 hours post-treatment (★ p = 0.008; ★ ★ p = 0.038; #p < 0.001) (A). Radiation sensitivity was determined by assaying for cell viability 72 hours post-treatment (★ p = 0.003; ★ ★ p = 0.026; ★ ★ ★ p = 0.002) (B) and by determining colony forming ability (★ p = 0.01; ★ ★ p = 0.009; ★ ★ ★ p < 0.001) (C).
Mentions: To determine whether tumorspheres cells preferentially survive after treatment with chemotherapeutic agents, tumorspheres were dissociated into single cells and treated with increasing concentrations of the cancer chemotherapeutic drug, doxorubicin. Doxorubicin is an anti-tumor antibiotic DNA damaging agent and is commonly used in veterinary and human cancer chemotherapy protocols. We used doses of Doxorubicin in cell culture experiments that correlate to concentrations that can be achieved in vivo. Cell viability was assayed 72 hours after treatment. Cells from tumorspheres demonstrated a significantly increased resistance to the cytotoxic effect of doxorubicin compared to parental adherent cells (Figure 2A).

Bottom Line: Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs.Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype.Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

View Article: PubMed Central - PubMed

Affiliation: Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK. lisa.pang@ed.ac.uk.

ABSTRACT
Canine mammary carcinoma is the most common cancer among female dogs and is often fatal due to the development of distant metastases. In humans, solid tumors are made up of heterogeneous cell populations, which perform different roles in the tumor economy. A small subset of tumor cells can hold or acquire stem cell characteristics, enabling them to drive tumor growth, recurrence and metastasis. In veterinary medicine, the molecular drivers of canine mammary carcinoma are as yet undefined. Here we report that putative cancer stem cells (CSCs) can be isolated form a canine mammary carcinoma cell line, REM134. We show that these cells have an increased ability to form tumorspheres, a characteristic of stem cells, and that they express embryonic stem cell markers associated with pluripotency. Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs. The epithelial to mesenchymal transition (EMT) has been associated with cancer invasion, metastasis, and the acquisition of stem cell characteristics. Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype. Furthermore, we show that canine mammary cancer cells can be induced to undergo EMT by TGFβ and that these cells have an increased ability to form tumorspheres. Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

No MeSH data available.


Related in: MedlinePlus