Biomedical subjects

Thomas N Wang

Publications and source records attributed to Thomas N Wang.

4 recordsLinked to original sources

PubMed2005

Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion.

BACKGROUND: Human CC chemokine Macrophage Inflammatory Protein-3alpha (MIP-3alpha) directs inflammatory cell migration through its binding to the transmembrane receptor CCR6. MIP-3alpha has recently been shown to promote tumor cell migration in pancreatic adenocarcinoma by up-regulation of matrix metalloproteinases (MMPs). We hypothesized that MIP-3alpha promotes pancreatic cancer invasion through the up-regulation of MMP-9, a Type 4 collagenase. MATERIALS, METHODS, AND RESULTS: Immunohistochemistry and RT-PCR confirmed the presence of MIP-3alpha in PANC-1 cells, a human pancreatic adenocarcinoma cell line. MIP-3alpha stimulated the production of both latent and active forms of MMP-9 in PANC-1 by Western analysis. Tumor cell invasion was then evaluated using a modified Boyden chamber invasion assay. MIP-3alpha promoted a dose-dependent increase in pancreatic cancer cell invasion (P < 0.05) at 100 ng/ml. The activity at the putative MIP-3alpha receptor, CCR6, was demonstrated by receptor blockade. Anti-CCR6 antibody and anti-MMP-9 antibody inhibited MIP-3alpha-stimulated PANC-1 cell invasion of collagen to 37% and 35% of control, respectively (P < 0.05). CONCLUSIONS: MIP-3alpha, through its CCR6 receptor, promotes tumor cell invasion by the up-regulation of MMP-9. Molecular based therapy aimed at the inhibition of MIP-3alpha activity through the CCR6 receptor may serve as a future target to prevent tumor cell invasion in pancreatic adenocarcinoma.

Cell Line, Tumor↗

PubMed2004

Antiangiogenic therapy.

Angiogenesis, the formation of blood vessels from preexisting ones, plays a crucial role in tumor progression. Activation of an "angiogenic switch" allows tumor cells to invade and metastasize. The growing interest in the use of antiangiogenic agents in the treatment and prevention of cancer lies in the theoretical advantages of this molecularly targeted modality of chemotherapy. Delivery of antiangiogenic agents are not complicated by having to penetrate large bulky masses but, instead, have easy access to tumoral endothelial cells. Antiangiogenic drugs may not cause cytopenias and thus will avoid many of the unwarranted toxicities of standard chemotherapeutic agents. Because they act directly on nascent endothelial cells, antiangiogenic agents may avoid tumor resistance mechanisms. If antiangiogenic agents are successful, they might be applicable to many tumor types and not be dependent on cell type or growth fraction of cells within a tumor. However, several important obstacles remain with regards to using antiangiogenic drugs in clinical trials with which we must contend in order to determine accurately the efficacy of these agents. In this article, we review the different classes of antiangiogenic agents available, ongoing clinical trials, as well as potential pitfalls and future directions in this exciting field.

Angiogenesis Inhibitors↗

PubMed2002

Fibroblasts promote breast cancer cell invasion by upregulating tumor matrix metalloproteinase-9 production.

BACKGROUND: Thrombospondin-1 (TSP-1) promotes breast cancer cell invasion of collagen by upregulating matrix metalloproteinase-9 (MMP-9) production. Stromal TSP-1 may play a role in regulating tumor cell invasion. We hypothesize that fibroblasts promote breast cancer cell invasion by upregulating the production of MMP-9 through TSP-1. METHODS: MDA-MB-231 human breast carcinoma cells were grown alone or in coculture with human fibroblasts. Gelatin zymography and Western immunoblot analysis for MMP-9 were performed on the coculture cell media and the single cell media. Inhibition of fibroblast-mediated breast tumor cell invasion by an anti-TSP-1 or an anti-MMP-9 antibody was evaluated using a modified Boyden chamber. RESULTS: Coculture experiments showed an increased production of MMP-9 when compared with breast cancer single cell culture or fibroblast single cell culture experiments as demonstrated by zymography and Western immunoblot analysis. Fibroblast-stimulated MMP-9 production was comparable with TSP-1-stimulated MMP-9 production. Anti-TSP-1 antibody and anti-MMP-9 antibody inhibited fibroblast-stimulated tumor cell invasion to 30% and 26% of controls, respectively (P <.05). CONCLUSIONS: Fibroblasts may regulate breast cancer cell invasion by promoting tumor MMP-9 production through TSP-1. Inhibition of stromal TSP-1 stimulation of MMP-9 synthesis may prevent matrix degradation necessary for tumor invasion and metastasis.

Antibodies↗

PubMedDate not supplied

Co-localization of macrophage inflammatory protein-3alpha (Mip-3alpha) and its receptor, CCR6, promotes pancreatic cancer cell invasion.

PURPOSE: Macrophage inflammatory protein-3alpha (Mip-3alpha) is par t of a family of chemotactic cytokines involved in recruiting inflammatory cells throughout the body. CCR6 is a G-protein-linked, seven-transmembrane receptor that is highly specific for Mip-3alpha. The role of Mip-3alpha has been well defined in several inflammatory conditions, but its role has not been well defined in neoplastic processes. Mip-3alpha has been shown to promote pancreatic cancer cell migration, but no studies have demonstrated the effect of Mip-3alpha on pancreatic cancer cell invasion. We hypothesize that Mip-3alpha and its CCR6 receptor promote pancreatic cancer cell invasion. MATERIALS AND METHODS: Immunohistochemical staining was per formed for Mip-3alpha and CCR6 in pancreatic cancer tissue and the human pancreatic cancer cell line PANC-1. RNA was isolated from PANC-1 cancer cells, and the presence of Mip-3alpha messenger RNA in PANC-1 cancer cells was determined by reverse transcriptase polymerase chain reaction. PANC-1 cancer cell invasion of type IV collagen was evaluated in the presence of Mip-3alpha and anti-CCR6 antibody with the use of a modified Boyden chamber invasion assay. RESULTS: Co-localization of Mip-3alpha and its CCR6 receptor in pancreatic cancer was confirmed using immunohistochemical staining for Mip-3alpha and its CCR6 receptor and reverse transcriptase polymerase chain reaction for Mip-3alpha. Immunohistochemical staining of pancreatic cancer tissue and the PANC-1 cancer cell line showed positive staining for Mip-3alpha and its CCR6 receptor within the cancer cells. Staining was also positive for Mip-3alpha within stromal cells adjacent to the cancer cells in pancreatic cancer tissue. Reverse transcriptase polymerase chain reaction demonstrated the presence of Mip-3alpha messenger RNA within PANC-1 cancer cells. Invasion studies showed that increasing concentrations of Mip-3alpha promoted a dose-dependent increase in pancreatic cancer cell invasion of type IV collagen. The addition of 100 ng/mL of Mip-3alpha promoted a threefold increase in pancreatic cancer cell invasion over that of the control group. Anti-CCR6 antibody inhibited Mip-3alpha-stimulated PANC-1 cancer cell invasion of type IV collagen by 63%. DISCUSSION: Co-localization of Mip-3alpha and its CCR6 receptor promotes pancreatic cancer cell invasion of type IV collagen. This finding continues to highlight the importance that inflammation plays in the progression of pancreatic cancer. As the relationship between the inflammatory and neoplastic processes involved with pancreatic cancer becomes better defined, therapies targeting the inflammatory process may help prevent pancreatic cancer invasion and metastasis.

Adenocarcinoma↗