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Tumours with PI3K activation are resistant to dietary restriction.

Kalaany NY, Sabatini DM - Nature (2009)

Bottom Line: Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown.Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1.Dietary restriction does not affect a PTEN- mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling.

View Article: PubMed Central - PubMed

Affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN- cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN- mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies.

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A K-RAS mouse model of lung cancer but not a PTEN- model of prostate cancer is sensitive to DRa, Representative images of lungs and average diameter of tumour nodules on the surface of the lungs (graph) of 7-week-old K-RASLA2; P53 LSL/ WT mice under AL or DR conditions (n=3). b-d, H&E staining (b) and immunohistochemical analyses of Ki-67 (c) and cleaved caspase-3 (d) in sections prepared from lungs in a. e-h, H&E staining (e) and immunohistochemical analyses of phospho-Akt S473 (f), Ki-67 (g), and cleaved caspase-3 (h) in prostates of 11-week-old Probasin-Cre; PTEN L/L mice under AL or DR conditions. In c, d, g, and h, graphs to right of respective images indicate percent of total cells that are positive for Ki-67 or cleaved caspase-3. Graphs show means ± s.e.m. of percent of proliferating (c and g) or apoptotic cells (d and h) measured in 10 images (1000 nuclei counted per image) from 2 different tumours per group. All pictures were captured under the same magnification and scale bar = 20 µm. ** indicates P = 8.3 × 10−8.
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Figure 5: A K-RAS mouse model of lung cancer but not a PTEN- model of prostate cancer is sensitive to DRa, Representative images of lungs and average diameter of tumour nodules on the surface of the lungs (graph) of 7-week-old K-RASLA2; P53 LSL/ WT mice under AL or DR conditions (n=3). b-d, H&E staining (b) and immunohistochemical analyses of Ki-67 (c) and cleaved caspase-3 (d) in sections prepared from lungs in a. e-h, H&E staining (e) and immunohistochemical analyses of phospho-Akt S473 (f), Ki-67 (g), and cleaved caspase-3 (h) in prostates of 11-week-old Probasin-Cre; PTEN L/L mice under AL or DR conditions. In c, d, g, and h, graphs to right of respective images indicate percent of total cells that are positive for Ki-67 or cleaved caspase-3. Graphs show means ± s.e.m. of percent of proliferating (c and g) or apoptotic cells (d and h) measured in 10 images (1000 nuclei counted per image) from 2 different tumours per group. All pictures were captured under the same magnification and scale bar = 20 µm. ** indicates P = 8.3 × 10−8.

Mentions: We next examined the effects of DR in two engineered mouse models of cancer. The first model (Probasin-Cre; PTEN L/L) is driven by PTEN loss in the prostate and recapitulates human prostate cancer progression31. The second (K-RASLA2; P53 LSL/ WT) is driven by K-ras activation as well as p53 heterozygosity and leads to the development of lung adenocarcinoma32,33. Compared to the AL condition, DR significantly reduced the size of tumour nodules (42% decrease) in the lungs of 7 week-old K-RASLA2; P53 LSL/ WT mice (Fig. 5a). Although the lung tumours were of similar pathological grade under both the AL feeding and DR (Fig. 5b), DR strongly decreased the number of proliferating tumour cells (4-fold; 12.5% to 3.1%; p = 8 × 10−8) without affecting the rates of apoptosis (Fig. 5c, d).


Tumours with PI3K activation are resistant to dietary restriction.

Kalaany NY, Sabatini DM - Nature (2009)

A K-RAS mouse model of lung cancer but not a PTEN- model of prostate cancer is sensitive to DRa, Representative images of lungs and average diameter of tumour nodules on the surface of the lungs (graph) of 7-week-old K-RASLA2; P53 LSL/ WT mice under AL or DR conditions (n=3). b-d, H&E staining (b) and immunohistochemical analyses of Ki-67 (c) and cleaved caspase-3 (d) in sections prepared from lungs in a. e-h, H&E staining (e) and immunohistochemical analyses of phospho-Akt S473 (f), Ki-67 (g), and cleaved caspase-3 (h) in prostates of 11-week-old Probasin-Cre; PTEN L/L mice under AL or DR conditions. In c, d, g, and h, graphs to right of respective images indicate percent of total cells that are positive for Ki-67 or cleaved caspase-3. Graphs show means ± s.e.m. of percent of proliferating (c and g) or apoptotic cells (d and h) measured in 10 images (1000 nuclei counted per image) from 2 different tumours per group. All pictures were captured under the same magnification and scale bar = 20 µm. ** indicates P = 8.3 × 10−8.
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Figure 5: A K-RAS mouse model of lung cancer but not a PTEN- model of prostate cancer is sensitive to DRa, Representative images of lungs and average diameter of tumour nodules on the surface of the lungs (graph) of 7-week-old K-RASLA2; P53 LSL/ WT mice under AL or DR conditions (n=3). b-d, H&E staining (b) and immunohistochemical analyses of Ki-67 (c) and cleaved caspase-3 (d) in sections prepared from lungs in a. e-h, H&E staining (e) and immunohistochemical analyses of phospho-Akt S473 (f), Ki-67 (g), and cleaved caspase-3 (h) in prostates of 11-week-old Probasin-Cre; PTEN L/L mice under AL or DR conditions. In c, d, g, and h, graphs to right of respective images indicate percent of total cells that are positive for Ki-67 or cleaved caspase-3. Graphs show means ± s.e.m. of percent of proliferating (c and g) or apoptotic cells (d and h) measured in 10 images (1000 nuclei counted per image) from 2 different tumours per group. All pictures were captured under the same magnification and scale bar = 20 µm. ** indicates P = 8.3 × 10−8.
Mentions: We next examined the effects of DR in two engineered mouse models of cancer. The first model (Probasin-Cre; PTEN L/L) is driven by PTEN loss in the prostate and recapitulates human prostate cancer progression31. The second (K-RASLA2; P53 LSL/ WT) is driven by K-ras activation as well as p53 heterozygosity and leads to the development of lung adenocarcinoma32,33. Compared to the AL condition, DR significantly reduced the size of tumour nodules (42% decrease) in the lungs of 7 week-old K-RASLA2; P53 LSL/ WT mice (Fig. 5a). Although the lung tumours were of similar pathological grade under both the AL feeding and DR (Fig. 5b), DR strongly decreased the number of proliferating tumour cells (4-fold; 12.5% to 3.1%; p = 8 × 10−8) without affecting the rates of apoptosis (Fig. 5c, d).

Bottom Line: Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown.Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1.Dietary restriction does not affect a PTEN- mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling.

View Article: PubMed Central - PubMed

Affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN- cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN- mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies.

Show MeSH
Related in: MedlinePlus