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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

Treatment of canine mammary carcinoma cells with TGFβ can induce an epithelial to mesenchymal transition, as indicated by changes in cell morphology (A), protein expression levels (B), and increased migration ability (★ p = 0.018; #p = 0.014; ★ ★ p = 0.004; ##p = 0.002; up = 0.001) (C, D).
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f4-cancers-03-01744: Treatment of canine mammary carcinoma cells with TGFβ can induce an epithelial to mesenchymal transition, as indicated by changes in cell morphology (A), protein expression levels (B), and increased migration ability (★ p = 0.018; #p = 0.014; ★ ★ p = 0.004; ##p = 0.002; up = 0.001) (C, D).

Mentions: Previous studies have shown that EMT activation of human neoplastic mammary epithelial cells is associated with enrichment of cells with stem-like properties [31]. Here we have shown that canine tumorspheres have a mesenchymal phenotype and increased invasiveness, and may have undergone EMT. To investigate if an experimentally induced EMT in canine mammary carcinoma cells can also result in enrichment of putative cancer stem cells, we treated these cells with TGFβ, a potent inducer of EMT. Within 72 hours of treatment with TGFβ, the cells show a clearly manifested morphological change. The untreated cells are characterized by a cobblestone appearance whereas TGFβ treated cells have an elongate fibroblastic phenotype indicative of mesenchymal cells (Figure 4A). The morphological change is associated with changes in protein expression of molecular markers of EMT. In the TGFβ treated cells there is a decrease in the epithelial markers E-cadherin and β-catenin, and an up regulation of the mesenchymal markers Fibronectin and Twist (Figure 4B). This data supports the hypothesis that TGFβ can activate EMT in canine cells.


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)

Treatment of canine mammary carcinoma cells with TGFβ can induce an epithelial to mesenchymal transition, as indicated by changes in cell morphology (A), protein expression levels (B), and increased migration ability (★ p = 0.018; #p = 0.014; ★ ★ p = 0.004; ##p = 0.002; up = 0.001) (C, D).
© Copyright Policy
Related In: Results  -  Collection

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

f4-cancers-03-01744: Treatment of canine mammary carcinoma cells with TGFβ can induce an epithelial to mesenchymal transition, as indicated by changes in cell morphology (A), protein expression levels (B), and increased migration ability (★ p = 0.018; #p = 0.014; ★ ★ p = 0.004; ##p = 0.002; up = 0.001) (C, D).
Mentions: Previous studies have shown that EMT activation of human neoplastic mammary epithelial cells is associated with enrichment of cells with stem-like properties [31]. Here we have shown that canine tumorspheres have a mesenchymal phenotype and increased invasiveness, and may have undergone EMT. To investigate if an experimentally induced EMT in canine mammary carcinoma cells can also result in enrichment of putative cancer stem cells, we treated these cells with TGFβ, a potent inducer of EMT. Within 72 hours of treatment with TGFβ, the cells show a clearly manifested morphological change. The untreated cells are characterized by a cobblestone appearance whereas TGFβ treated cells have an elongate fibroblastic phenotype indicative of mesenchymal cells (Figure 4A). The morphological change is associated with changes in protein expression of molecular markers of EMT. In the TGFβ treated cells there is a decrease in the epithelial markers E-cadherin and β-catenin, and an up regulation of the mesenchymal markers Fibronectin and Twist (Figure 4B). This data supports the hypothesis that TGFβ can activate EMT in canine cells.

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