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An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.

Donatello S, Hudson L, Cottell DC, Blanco A, Aurrekoetxea I, Shelly MJ, Dervan PA, Kell MR, Stokes M, Hill AD, Hopkins AM - J. Exp. Clin. Cancer Res. (2011)

Bottom Line: Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively.The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumorigenic MCF-10A cells.Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Royal College of Surgeons in Ireland; Dublin, Ireland.

ABSTRACT

Background: Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.

Methods: Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively.

Results: Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumorigenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells.

Conclusions: Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

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Progenitor imbalance model. A normal phenotype likely requires a fine balance between different progenitor populations (DP and DN). In normal cells, a balance between proliferation and senescence interplays with a balance between these putative progenitor populations. This promotes regulated generation of differentiated cells. In aggressive tumours, increased proliferation and decreased senescence influences the equilibrium between different progenitor populations. This may alter the differentiated/undifferentiated cell balance, promoting basal-like phenotypes associated with tumour progression.
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Figure 5: Progenitor imbalance model. A normal phenotype likely requires a fine balance between different progenitor populations (DP and DN). In normal cells, a balance between proliferation and senescence interplays with a balance between these putative progenitor populations. This promotes regulated generation of differentiated cells. In aggressive tumours, increased proliferation and decreased senescence influences the equilibrium between different progenitor populations. This may alter the differentiated/undifferentiated cell balance, promoting basal-like phenotypes associated with tumour progression.

Mentions: We have reported reduced senescence in tumour versus non-tumour breast primary cultures, and stepwise increases in the proliferation:senescence ratio with increasing tumour grade. Isolation of putative progenitor subpopulations revealed a novel correlation between increased DN:DP ratios and clinicopathological indicators of aggressive tumours (HG, ER-negativity or HER2-positivity). Our data suggest that progenitor population imbalance could promote tumour progression by altering the relationship between proliferation and senescence (Figure 5). Future investigations relating clinicopathological factors to alterations in progenitor cell populations may be valuable in dissecting mechanisms associated with progenitor-driven breast tumour progression.


An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.

Donatello S, Hudson L, Cottell DC, Blanco A, Aurrekoetxea I, Shelly MJ, Dervan PA, Kell MR, Stokes M, Hill AD, Hopkins AM - J. Exp. Clin. Cancer Res. (2011)

Progenitor imbalance model. A normal phenotype likely requires a fine balance between different progenitor populations (DP and DN). In normal cells, a balance between proliferation and senescence interplays with a balance between these putative progenitor populations. This promotes regulated generation of differentiated cells. In aggressive tumours, increased proliferation and decreased senescence influences the equilibrium between different progenitor populations. This may alter the differentiated/undifferentiated cell balance, promoting basal-like phenotypes associated with tumour progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094256&req=5

Figure 5: Progenitor imbalance model. A normal phenotype likely requires a fine balance between different progenitor populations (DP and DN). In normal cells, a balance between proliferation and senescence interplays with a balance between these putative progenitor populations. This promotes regulated generation of differentiated cells. In aggressive tumours, increased proliferation and decreased senescence influences the equilibrium between different progenitor populations. This may alter the differentiated/undifferentiated cell balance, promoting basal-like phenotypes associated with tumour progression.
Mentions: We have reported reduced senescence in tumour versus non-tumour breast primary cultures, and stepwise increases in the proliferation:senescence ratio with increasing tumour grade. Isolation of putative progenitor subpopulations revealed a novel correlation between increased DN:DP ratios and clinicopathological indicators of aggressive tumours (HG, ER-negativity or HER2-positivity). Our data suggest that progenitor population imbalance could promote tumour progression by altering the relationship between proliferation and senescence (Figure 5). Future investigations relating clinicopathological factors to alterations in progenitor cell populations may be valuable in dissecting mechanisms associated with progenitor-driven breast tumour progression.

Bottom Line: Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively.The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumorigenic MCF-10A cells.Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Royal College of Surgeons in Ireland; Dublin, Ireland.

ABSTRACT

Background: Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.

Methods: Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively.

Results: Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumorigenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells.

Conclusions: Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

Show MeSH
Related in: MedlinePlus