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Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk.

Zito G, Saotome I, Liu Z, Ferro EG, Sun TY, Nguyen DX, Bilguvar K, Ko CJ, Greco V - Nat Commun (2014)

Bottom Line: A fundamental goal in cancer biology is to identify the cells and signalling pathways that are keys to induce tumour regression.Furthermore, we demonstrate that developmental programs utilized for skin hair follicle regeneration, such as Wnt, are hijacked to sustain tumour growth and that the retinoic acid (RA) signalling pathway promotes tumour regression by inhibiting Wnt signalling.Finally, we find that RA signalling can induce regression of malignant tumours that do not normally spontaneously regress, such as squamous cell carcinomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Yale Stem Cell Center, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut 06510, USA.

ABSTRACT
A fundamental goal in cancer biology is to identify the cells and signalling pathways that are keys to induce tumour regression. Here we use a spontaneously self-regressing tumour, cutaneous keratoacanthoma (KAs), to identify physiological mechanisms that drive tumour regression. By using a mouse model system that recapitulates the behaviour of human KAs, we show that self-regressing tumours shift their balance to a differentiation programme during regression. Furthermore, we demonstrate that developmental programs utilized for skin hair follicle regeneration, such as Wnt, are hijacked to sustain tumour growth and that the retinoic acid (RA) signalling pathway promotes tumour regression by inhibiting Wnt signalling. Finally, we find that RA signalling can induce regression of malignant tumours that do not normally spontaneously regress, such as squamous cell carcinomas. These findings provide new insights into the physiological mechanisms of tumour regression and suggest therapeutic strategies to induce tumour regression.

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Mouse KA tumours recapitulate human KAs and they originate from HFSC descendants.(a,b) Hematoxylin and eosin staining shows mouse KA in the growth phase and the regression phase (scale bar, 100 μm for pictures on the left, and 50 μm for pictures on the right). (c) Schematic representation of the genetic lineage tracing approach utilized for labelling the HFSCs. Representative image of a hair follicle from tamoxifen-treated Krt19CreER; Rosa26 mTmGFP mice. The fluorescent reporter (GFPr, in green) labels the stem cells and the progeny. Dotted bracket indicates the location of the stem cells within the hair follicle (scale bar, 20 μm). Flow cytometry analysis of GFP+ cells in the HFSC compartment prior to DMBA treatment (n=3). (d) DMBA was applied to tamoxifen-treated K19CreER; Rosa26mTmGFP mice. Twelve weeks post-DMBA treatment, GFP+ hair follicle descendant cells were found in the epithelium of KA tumours, as shown by GFP (green) co-localization with P-cadherin (red) (n=18, scale bar, 50 μm). (e,h) Sox9 staining in KA tumours sections during growth and regression phases (n=3, scale bar, 50 μm). (f) Immunofluorescence staining for Sox9 showing co-localization with the HFSCs-derived cells (HFSCs, green) after Cre recombination tamoxifen mediated. Continuous green lines identify the HFSC descendants (scale bar, 50 μm). (g,i) Immunofluorescence staining for the proliferation marker Ki67 in KAs tumours during growth and regression phase shows reduction in the number of Ki67+ (red) and P-cadherin+ (green) cells during regression (scale bar, 50 μm). Cell proliferation has been quantified in KA during growth or regression (n=4). Data are represented as mean±s.d., ****<0.001 obtained by unpaired t-test analysis. (j) Representative flow cytometry analysis of HFSC-derived GFP+ cells during KA growth and regression (n=7 and n=8, respectively). In all the pictures, dotted lines indicate the tumour/stroma interface. In all the immunofluorescence experiments performed, nuclei are marked in blue with DAPI.
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f1: Mouse KA tumours recapitulate human KAs and they originate from HFSC descendants.(a,b) Hematoxylin and eosin staining shows mouse KA in the growth phase and the regression phase (scale bar, 100 μm for pictures on the left, and 50 μm for pictures on the right). (c) Schematic representation of the genetic lineage tracing approach utilized for labelling the HFSCs. Representative image of a hair follicle from tamoxifen-treated Krt19CreER; Rosa26 mTmGFP mice. The fluorescent reporter (GFPr, in green) labels the stem cells and the progeny. Dotted bracket indicates the location of the stem cells within the hair follicle (scale bar, 20 μm). Flow cytometry analysis of GFP+ cells in the HFSC compartment prior to DMBA treatment (n=3). (d) DMBA was applied to tamoxifen-treated K19CreER; Rosa26mTmGFP mice. Twelve weeks post-DMBA treatment, GFP+ hair follicle descendant cells were found in the epithelium of KA tumours, as shown by GFP (green) co-localization with P-cadherin (red) (n=18, scale bar, 50 μm). (e,h) Sox9 staining in KA tumours sections during growth and regression phases (n=3, scale bar, 50 μm). (f) Immunofluorescence staining for Sox9 showing co-localization with the HFSCs-derived cells (HFSCs, green) after Cre recombination tamoxifen mediated. Continuous green lines identify the HFSC descendants (scale bar, 50 μm). (g,i) Immunofluorescence staining for the proliferation marker Ki67 in KAs tumours during growth and regression phase shows reduction in the number of Ki67+ (red) and P-cadherin+ (green) cells during regression (scale bar, 50 μm). Cell proliferation has been quantified in KA during growth or regression (n=4). Data are represented as mean±s.d., ****<0.001 obtained by unpaired t-test analysis. (j) Representative flow cytometry analysis of HFSC-derived GFP+ cells during KA growth and regression (n=7 and n=8, respectively). In all the pictures, dotted lines indicate the tumour/stroma interface. In all the immunofluorescence experiments performed, nuclei are marked in blue with DAPI.

Mentions: In order to dissect the cellular mechanisms that sustain self-regressing KA tumour formation, we used a DMBA (7,12-dimethylbenz(a)anthracene) based chemical carcinogenetic protocol on mice11. Repeated applications of DMBA on the mouse back skin twice a week for up to 20 weeks led to a variety of skin epithelial tumours of which 40% were self-regressing KAs (Supplementary Fig. 1a,b). These epithelial self-regressing tumours mimicked the human variant (Fig. 1a,b; Supplementary Fig. 1c)4. Reproducibly, DMBA withdrawal led to KA tumour regression within 6–8 weeks post-DMBA treatment therefore providing a robust model for studying the mechanisms that drive tumour regression.


Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk.

Zito G, Saotome I, Liu Z, Ferro EG, Sun TY, Nguyen DX, Bilguvar K, Ko CJ, Greco V - Nat Commun (2014)

Mouse KA tumours recapitulate human KAs and they originate from HFSC descendants.(a,b) Hematoxylin and eosin staining shows mouse KA in the growth phase and the regression phase (scale bar, 100 μm for pictures on the left, and 50 μm for pictures on the right). (c) Schematic representation of the genetic lineage tracing approach utilized for labelling the HFSCs. Representative image of a hair follicle from tamoxifen-treated Krt19CreER; Rosa26 mTmGFP mice. The fluorescent reporter (GFPr, in green) labels the stem cells and the progeny. Dotted bracket indicates the location of the stem cells within the hair follicle (scale bar, 20 μm). Flow cytometry analysis of GFP+ cells in the HFSC compartment prior to DMBA treatment (n=3). (d) DMBA was applied to tamoxifen-treated K19CreER; Rosa26mTmGFP mice. Twelve weeks post-DMBA treatment, GFP+ hair follicle descendant cells were found in the epithelium of KA tumours, as shown by GFP (green) co-localization with P-cadherin (red) (n=18, scale bar, 50 μm). (e,h) Sox9 staining in KA tumours sections during growth and regression phases (n=3, scale bar, 50 μm). (f) Immunofluorescence staining for Sox9 showing co-localization with the HFSCs-derived cells (HFSCs, green) after Cre recombination tamoxifen mediated. Continuous green lines identify the HFSC descendants (scale bar, 50 μm). (g,i) Immunofluorescence staining for the proliferation marker Ki67 in KAs tumours during growth and regression phase shows reduction in the number of Ki67+ (red) and P-cadherin+ (green) cells during regression (scale bar, 50 μm). Cell proliferation has been quantified in KA during growth or regression (n=4). Data are represented as mean±s.d., ****<0.001 obtained by unpaired t-test analysis. (j) Representative flow cytometry analysis of HFSC-derived GFP+ cells during KA growth and regression (n=7 and n=8, respectively). In all the pictures, dotted lines indicate the tumour/stroma interface. In all the immunofluorescence experiments performed, nuclei are marked in blue with DAPI.
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f1: Mouse KA tumours recapitulate human KAs and they originate from HFSC descendants.(a,b) Hematoxylin and eosin staining shows mouse KA in the growth phase and the regression phase (scale bar, 100 μm for pictures on the left, and 50 μm for pictures on the right). (c) Schematic representation of the genetic lineage tracing approach utilized for labelling the HFSCs. Representative image of a hair follicle from tamoxifen-treated Krt19CreER; Rosa26 mTmGFP mice. The fluorescent reporter (GFPr, in green) labels the stem cells and the progeny. Dotted bracket indicates the location of the stem cells within the hair follicle (scale bar, 20 μm). Flow cytometry analysis of GFP+ cells in the HFSC compartment prior to DMBA treatment (n=3). (d) DMBA was applied to tamoxifen-treated K19CreER; Rosa26mTmGFP mice. Twelve weeks post-DMBA treatment, GFP+ hair follicle descendant cells were found in the epithelium of KA tumours, as shown by GFP (green) co-localization with P-cadherin (red) (n=18, scale bar, 50 μm). (e,h) Sox9 staining in KA tumours sections during growth and regression phases (n=3, scale bar, 50 μm). (f) Immunofluorescence staining for Sox9 showing co-localization with the HFSCs-derived cells (HFSCs, green) after Cre recombination tamoxifen mediated. Continuous green lines identify the HFSC descendants (scale bar, 50 μm). (g,i) Immunofluorescence staining for the proliferation marker Ki67 in KAs tumours during growth and regression phase shows reduction in the number of Ki67+ (red) and P-cadherin+ (green) cells during regression (scale bar, 50 μm). Cell proliferation has been quantified in KA during growth or regression (n=4). Data are represented as mean±s.d., ****<0.001 obtained by unpaired t-test analysis. (j) Representative flow cytometry analysis of HFSC-derived GFP+ cells during KA growth and regression (n=7 and n=8, respectively). In all the pictures, dotted lines indicate the tumour/stroma interface. In all the immunofluorescence experiments performed, nuclei are marked in blue with DAPI.
Mentions: In order to dissect the cellular mechanisms that sustain self-regressing KA tumour formation, we used a DMBA (7,12-dimethylbenz(a)anthracene) based chemical carcinogenetic protocol on mice11. Repeated applications of DMBA on the mouse back skin twice a week for up to 20 weeks led to a variety of skin epithelial tumours of which 40% were self-regressing KAs (Supplementary Fig. 1a,b). These epithelial self-regressing tumours mimicked the human variant (Fig. 1a,b; Supplementary Fig. 1c)4. Reproducibly, DMBA withdrawal led to KA tumour regression within 6–8 weeks post-DMBA treatment therefore providing a robust model for studying the mechanisms that drive tumour regression.

Bottom Line: A fundamental goal in cancer biology is to identify the cells and signalling pathways that are keys to induce tumour regression.Furthermore, we demonstrate that developmental programs utilized for skin hair follicle regeneration, such as Wnt, are hijacked to sustain tumour growth and that the retinoic acid (RA) signalling pathway promotes tumour regression by inhibiting Wnt signalling.Finally, we find that RA signalling can induce regression of malignant tumours that do not normally spontaneously regress, such as squamous cell carcinomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Yale Stem Cell Center, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut 06510, USA.

ABSTRACT
A fundamental goal in cancer biology is to identify the cells and signalling pathways that are keys to induce tumour regression. Here we use a spontaneously self-regressing tumour, cutaneous keratoacanthoma (KAs), to identify physiological mechanisms that drive tumour regression. By using a mouse model system that recapitulates the behaviour of human KAs, we show that self-regressing tumours shift their balance to a differentiation programme during regression. Furthermore, we demonstrate that developmental programs utilized for skin hair follicle regeneration, such as Wnt, are hijacked to sustain tumour growth and that the retinoic acid (RA) signalling pathway promotes tumour regression by inhibiting Wnt signalling. Finally, we find that RA signalling can induce regression of malignant tumours that do not normally spontaneously regress, such as squamous cell carcinomas. These findings provide new insights into the physiological mechanisms of tumour regression and suggest therapeutic strategies to induce tumour regression.

Show MeSH
Related in: MedlinePlus