Limits...
Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis.

Ortiz B, White JR, Wu WH, Chan TA - Oncotarget (2014)

Bottom Line: PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers.PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together.Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Gerstner Sloan-Kettering Graduate School, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

ABSTRACT
PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.

Show MeSH

Related in: MedlinePlus

Lymphomas in mice with Ptprd and Cdkn2a loss(A) Representative images of Ptprd+/−Cdkn2a−/− B-cell lymphoma in a mesenteric lymph node. Left, scale bar = 100μm; Middle, B220 staining is used to identify B-cells, scale bar = 50μm; Right, CD3 staining is used to identify T-cells, scale bar = 50μm. (B) Representative images of Ptprd−/−Cdkn2a−/− T-cell lymphoma in the small intestine. Left, scale bar = 100μm; Middle, B220 staining, scale bar = 100μm; Right, CD3 staining, scale bar = 100μm. (C) Lymphomas in Ptprd+/−Cdkn2a−/− or Ptprd−/−Cdkn2a−/− mice have similar proliferative indices. Age-matched mesenteric lymph nodes with and without lymphoma were stained with Ki67 by immunohistochemistry.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4196177&req=5

Figure 4: Lymphomas in mice with Ptprd and Cdkn2a loss(A) Representative images of Ptprd+/−Cdkn2a−/− B-cell lymphoma in a mesenteric lymph node. Left, scale bar = 100μm; Middle, B220 staining is used to identify B-cells, scale bar = 50μm; Right, CD3 staining is used to identify T-cells, scale bar = 50μm. (B) Representative images of Ptprd−/−Cdkn2a−/− T-cell lymphoma in the small intestine. Left, scale bar = 100μm; Middle, B220 staining, scale bar = 100μm; Right, CD3 staining, scale bar = 100μm. (C) Lymphomas in Ptprd+/−Cdkn2a−/− or Ptprd−/−Cdkn2a−/− mice have similar proliferative indices. Age-matched mesenteric lymph nodes with and without lymphoma were stained with Ki67 by immunohistochemistry.

Mentions: We next determined whether Ptprd and Cdkn2a deletion altered the resultant tumor spectrum. Interestingly, Ptprd−/−Cdkn2a−/− mice developed significantly more lymphomas than Ptprd+/+Cdkn2a−/− mice (Figure 3B, p<0.05). In addition, Ptprd+/−Cdkn2a−/− mice showed a trend toward developing more lymphomas than Ptprd+/+Cdkn2a−/− mice (Figure 3B). Figure 4A and B shows examples of hematoxylin and eosin stained lymphomas in the mesenteric lymph node and small intestine, respectively. These tumors were composed of sheets of discrete round cells with scant basophilic cytoplasm and large round to polygonal nuclei. The neoplastic infiltrates often effaced normal tissue architecture, particularly within the lymph nodes (Figure 4A). In order to determine the cell origin of the lymphomas, we stained the tumors for B220, a B-cell marker, and CD3, a T-cell marker (Figure 4A, B). As listed in Table S2, all Ptprd+/−Cdkn2a−/− lymphomas were of a B-cell origin. Interestingly, 2/3 of the Ptprd−/−Cdkn2a−/− tumors were of T-cell origin (Table S2, Figure 4B). In order to quantitate the proliferative index of lymphoma cells, mesenteric lymph nodes from age-matched (28-39 weeks old) mice with or without lymphoma were stained for Ki67. Lymphomas from Ptprd+/−Cdkn2a−/− mice and Ptprd−/−Cdkn2a−/− mice had increased Ki67 staining, confirming the proliferative nature of the lymphomas (Figure 4C). Lymphomas from Ptprd+/−Cdkn2a−/− and Ptprd−/−Cdkn2a−/− mice had similar levels of Ki67 staining. Our results indicate that loss of Ptprd in Cdkn2a mice promotes the development of lymphomas.


Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis.

Ortiz B, White JR, Wu WH, Chan TA - Oncotarget (2014)

Lymphomas in mice with Ptprd and Cdkn2a loss(A) Representative images of Ptprd+/−Cdkn2a−/− B-cell lymphoma in a mesenteric lymph node. Left, scale bar = 100μm; Middle, B220 staining is used to identify B-cells, scale bar = 50μm; Right, CD3 staining is used to identify T-cells, scale bar = 50μm. (B) Representative images of Ptprd−/−Cdkn2a−/− T-cell lymphoma in the small intestine. Left, scale bar = 100μm; Middle, B220 staining, scale bar = 100μm; Right, CD3 staining, scale bar = 100μm. (C) Lymphomas in Ptprd+/−Cdkn2a−/− or Ptprd−/−Cdkn2a−/− mice have similar proliferative indices. Age-matched mesenteric lymph nodes with and without lymphoma were stained with Ki67 by immunohistochemistry.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196177&req=5

Figure 4: Lymphomas in mice with Ptprd and Cdkn2a loss(A) Representative images of Ptprd+/−Cdkn2a−/− B-cell lymphoma in a mesenteric lymph node. Left, scale bar = 100μm; Middle, B220 staining is used to identify B-cells, scale bar = 50μm; Right, CD3 staining is used to identify T-cells, scale bar = 50μm. (B) Representative images of Ptprd−/−Cdkn2a−/− T-cell lymphoma in the small intestine. Left, scale bar = 100μm; Middle, B220 staining, scale bar = 100μm; Right, CD3 staining, scale bar = 100μm. (C) Lymphomas in Ptprd+/−Cdkn2a−/− or Ptprd−/−Cdkn2a−/− mice have similar proliferative indices. Age-matched mesenteric lymph nodes with and without lymphoma were stained with Ki67 by immunohistochemistry.
Mentions: We next determined whether Ptprd and Cdkn2a deletion altered the resultant tumor spectrum. Interestingly, Ptprd−/−Cdkn2a−/− mice developed significantly more lymphomas than Ptprd+/+Cdkn2a−/− mice (Figure 3B, p<0.05). In addition, Ptprd+/−Cdkn2a−/− mice showed a trend toward developing more lymphomas than Ptprd+/+Cdkn2a−/− mice (Figure 3B). Figure 4A and B shows examples of hematoxylin and eosin stained lymphomas in the mesenteric lymph node and small intestine, respectively. These tumors were composed of sheets of discrete round cells with scant basophilic cytoplasm and large round to polygonal nuclei. The neoplastic infiltrates often effaced normal tissue architecture, particularly within the lymph nodes (Figure 4A). In order to determine the cell origin of the lymphomas, we stained the tumors for B220, a B-cell marker, and CD3, a T-cell marker (Figure 4A, B). As listed in Table S2, all Ptprd+/−Cdkn2a−/− lymphomas were of a B-cell origin. Interestingly, 2/3 of the Ptprd−/−Cdkn2a−/− tumors were of T-cell origin (Table S2, Figure 4B). In order to quantitate the proliferative index of lymphoma cells, mesenteric lymph nodes from age-matched (28-39 weeks old) mice with or without lymphoma were stained for Ki67. Lymphomas from Ptprd+/−Cdkn2a−/− mice and Ptprd−/−Cdkn2a−/− mice had increased Ki67 staining, confirming the proliferative nature of the lymphomas (Figure 4C). Lymphomas from Ptprd+/−Cdkn2a−/− and Ptprd−/−Cdkn2a−/− mice had similar levels of Ki67 staining. Our results indicate that loss of Ptprd in Cdkn2a mice promotes the development of lymphomas.

Bottom Line: PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers.PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together.Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Gerstner Sloan-Kettering Graduate School, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

ABSTRACT
PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.

Show MeSH
Related in: MedlinePlus