Clinicopathological implications of parathyroid hormone-related protein in human colorectal tumours

Nishihara, Minoru; Ito, Masahiro; Tomioka, Takahiro; Ohtsuru, Akira; Taguchi, Takashi; Kanematsu, Takashi

doi:10.1002/(sici)1096-9896(199901)187:2<217::aid-path210>3.0.co;2-0

Cited by 33 publications

(22 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PTHrP acts as an autocrine, paracrine, or intracrine factor in a wide range of developmental and physiological processes (7,8), it has growth-promoting and antiapoptotic properties (6), and it plays a crucial role in the development of the mammary gland and skeleton (8)(9)(10). Of special interest is the association of PTHrP with oncologic pathologies such as breast cancer (11,12) and lung (13)(14)(15), prostate (16)(17)(18), renal (19), colorectal (20)(21)(22), skin (23,24), and gastric carcinomas (25,26). Circulating levels of PTHrP generally correlate with the more advanced stages of cancer (20,(27)(28)(29)(30)(31)(32), and PTHrP regulates the expression of several tumor-relevant genes (33).…”

Section: Introductionmentioning

confidence: 99%

“…Of special interest is the association of PTHrP with oncologic pathologies such as breast cancer (11,12) and lung (13)(14)(15), prostate (16)(17)(18), renal (19), colorectal (20)(21)(22), skin (23,24), and gastric carcinomas (25,26). Circulating levels of PTHrP generally correlate with the more advanced stages of cancer (20,(27)(28)(29)(30)(31)(32), and PTHrP regulates the expression of several tumor-relevant genes (33). Despite the frequent association of PTHrP dysregulation with many tumor types, a precise and direct role for PTHrP in cancer development and progression has been difficult to prove, and its involvement in tumor initiation in vivo and in critical steps of malignant conversion is not clear.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Li¹,

Karaplis²,

Huang³

et al. 2011

J. Clin. Invest.

113

118

View full text Add to dashboard Cite

Parathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer -it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Li¹,

Karaplis²,

Huang³

et al. 2011

J. Clin. Invest.

113

118

View full text Add to dashboard Cite

show abstract

“…PTHrP is also expressed by cancer cells not typically associated with hypercalcemia [20][21][22][23][24]. It has been shown that PTHrP expression correlates with the severity of colon carcinomaspecifically, with cell differentiation, depth of invasion, lymphatic invasion, lymph node and hepatic metastasis, and Dukes' classification [21].…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that PTHrP expression correlates with the severity of colon carcinomaspecifically, with cell differentiation, depth of invasion, lymphatic invasion, lymph node and hepatic metastasis, and Dukes' classification [21]. We have previously shown that PTHrP increases the proliferation of the human colon cancer cell line LoVo [20].…”

Section: Introductionmentioning

confidence: 99%

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Shen¹,

Mula²,

Evers³

et al. 2007

Regulatory Peptides

View full text Add to dashboard Cite

Parathyroid hormone-related protein (PTHrP) has been localized in human colon cancer tissue and cell lines. We have previously shown that PTHrP increases colon cancer cell proliferation, extracellular matrix adhesion, and cell-surface integrin α6β4 expression. Since cancer cell migration, invasion, and survival are crucial components of metastasis, and colon cancer has a high metastatic potential, in this study we used the human colon cancer cell line LoVo as a model system to study the effects of PTHrP on these parameters. PTHrP expression was modulated by stable transfection with a construct expressing PTHrP (−36 to +139). We report that PTHrP increases cell migration, invasion, and survival. PTHrP altered cell morphology, with PTHrP-overexpressing cells exhibiting increased spreading and several long protrusions. PTHrP also increased the steady-state mRNA levels of the integrin α6 and β4 subunits, indicating a direct and/or indirect effect of PTHrP on the transcriptional and/or posttranscriptional regulation of integrin α6 and β4 expression. Integrin α6β4 activates the phosphoinositol 3-kinase (PI3-K)/Akt pathway, leading to glycogen synthase kinase-3 (GSK-3) deactivation. PTHrP overexpression also led to an increase in active Akt and inactive GSK-3 levels, indicating that the PTHrP-mediated upregulation of integrin α6β4 expression may activate the PI3-K pathway, resulting in increased cell survival, migration and invasion.

show abstract

“…One of these factors is parathyroid hormone-related protein (PTHrP). PTHrP expression correlates with the severity of colon carcinoma -specifically, with cell differentiation, depth of invasion, lymphatic invasion, lymph node and hepatic metastasis, and Dukes' classification [7]. The mechanisms through which PTHrP exerts its effects in colon cancer are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

PTHrP increases xenograft growth and promotes integrin α6β4 expression and Akt activation in colon cancer

et al. 2007

View full text Add to dashboard Cite

Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines. Expression of PTHrP and phosphatidylinositol 3-kinase (PI3-K) pathway components correlates with the severity of colon carcinoma. Here we observed a positive effect of endogenous PTHrP on LoVo (human colon cancer) cell proliferation, migration, invasion, integrin α6 and β4 expression, and p-Akt levels. There was a direct correlation between PTHrP expression and anchorage-independent cell growth. PTHrP significantly increased xenograft growth; tumors from PTHrP-overexpressing cells showed increased expression of integrins α6 and β4, and PI3-K pathway components. The higher expression of PTHrP in human colon cancer adenocarcinoma vs. normal colonic mucosa was accompanied by increased integrin α6 and β4 levels. Elevated PTHrP expression in colon cancer may thus upregulate integrin α6β4 expression, with consequent PI3-K activation. Targeting PTHrP might result in effective inhibition of tumor growth, migration and invasion.

show abstract

Clinicopathological implications of parathyroid hormone-related protein in human colorectal tumours

Cited by 33 publications

References 19 publications

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

PTHrP increases xenograft growth and promotes integrin α6β4 expression and Akt activation in colon cancer

Contact Info

Product

Resources

About