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Biomedical subjects

Wenhui Qiao

Publications and source records attributed to Wenhui Qiao.

6 recordsLinked to original sources
PubMed2006

Smad4 signalling in T cells is required for suppression of gastrointestinal cancer.

SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

Adenomatous Polyposis Coli↗
PubMed2006

The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors.

BRCA1 and BRCA2 mutations are responsible for most familial breast carcinomas. Recent reports carried out in non-cancerous mouse BRCA1- or BRCA2-deficient embryonic stem (ES) cells, and hamster BRCA2-deficient cells have demonstrated that the targeted inhibition of poly(ADP-ribose) polymerase (PARP-1) kills BRCA mutant cells with high specificity. Although these studies bring hope for BRCA mutation carriers, the effectiveness of PARP-1 inhibitors for breast cancer remains elusive. Here we present the first in vivo demonstration of PARP-1 activity in BRCA1-deficient mammary tumors and describe the effects of PARP-1 inhibitors (AG14361, NU1025, and 3-aminobenzamide) on BRCA1-deficient ES cells, mouse and human breast cancer cells. AG14361 was highly selective for BRCA1-/- ES cells; however, NU1025 and 3-aminobenzamide were relatively non-selective. In allografts of naïve ES BRCA1-/- cells there was either partial or complete remission of tumors. However, in allografts of mouse, BRCA1-/- mammary tumors, there was no tumor regression or remission although a partial inhibition of tumor growth was observed in both the BRCA1-/- and BRCA1+/+ allografts. In human tumor cells, PARP-1 inhibitors showed no difference in vitro in limiting the growth of mammary tumors irrespective of their BRCA1 status. These results suggest that PARP-1 inhibitors may non-specifically inhibit the growth of mammary tumors.

Aged↗
PubMed2006

Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.

Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.

Animals↗
PubMed2005

Effect of bilateral oophorectomy on mammary tumor formation in BRCA1 mutant mice.

Germline mutations of breast cancer-associated gene 1 (BRCA1) predispose women to breast and ovarian cancer. It was recently shown that bilateral oophorectomy decreases breast cancer incidence in BRCA1 mutation carriers. To model human BRCA1 carriers, our laboratory has previously created mice with a conditional knockout of the full-length BRCA1 gene in the mammary epithelium combined with a heterozygous knockout of the p53 tumor suppressor gene. These mice developed ER-negative mammary tumors and were employed to determine the effects of oophorectomy on tumor formation. Individual knockout mice (BRCA1(Co/Co) MMTV-Crep53+/-), following two complete pregnancies, were either oophorectomized or sham treated. Mice were subsequently examined for the development of palpable mammary tumors until they were 12 months of age. Until 135 days post-oophorectomy (255 days of age), the tumor incidence was similar in both oophorectomized and intact mice, approximately 30%. After this time, the increase in tumor incidence was much lower in the oophorectomized mice, while tumor incidence increased in non-oophorectomized mice. The effects of oophorectomy on mammary development in both control and knockout mice were also examined. Oophorectomized mice with a conditional knockout of full-length BRCA1 in conjunction with a loss of one p53 allele exhibited glandular regression with a reduction in the number of mammary epithelial cells following oophorectomy. This study employed a model that may be relevant for testing agents useful against breast cancer in BRCA1 carriers and a subset of sporadic cancers. The data also show that oophorectomy, if performed significantly prior to the time that tumors arise, appears to be quite effective.

Animals↗
PubMed2003

Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice.

Smad4 is a central mediator for TGFbeta signals, which play important functions in many biological processes. To study the role of Smad4 in mammary gland development and neoplasia, we disrupted this gene in mammary epithelium using a Cre-loxP approach. Smad4 is expressed in the mammary gland throughout development; however, its inactivation did not cause abnormal development of the gland during the first three pregnancies. Instead, lack of Smad4 gradually induced cell proliferation, alveolar hyperplasia and transdifferentiation of mammary epithelial cells into squamous epithelial cells. Consequently, all mutant mice developed squamous cell carcinoma and/or mammary abscesses between 5 and 16 months of age. We demonstrated that absence of Smad4 resulted in beta-catenin accumulation at onset and throughout the process of transdifferentiation, implicating beta-catenin, a key component of the Wnt signaling pathway, in the development of squamous metaplasia in Smad4-null mammary glands. We further demonstrated that TGFbeta1 treatment degraded beta-catenin and induced epithelial-mesenchymal transformation in cultured mammary epithelial cells. However, such actions were blocked in the absence of Smad4. These findings indicate that TGFbeta/Smad4 signals play a role in cell fate maintenance during mammary gland development and neoplasia.

Abscess↗