Identification of breast cancer metastasis-associated genes by chip technology.

In order to identify genes associated with metastasis of mammary carcinoma, we compared the transcriptional profile (Affymetrix chip technology) of two cell lines derived from primary mammary carcinoma, three cell lines derived from bone marrow micrometastasis, a cell line derived from a lymph node metastasis as well as a cell line derived from malignant ascites. We found that 11 genes (0.16%) were up-regulated in all five cell lines derived from metastasis and 32 genes (0.45%) were up-regulated in four of these cell lines. Sixteen genes (0.23%) were down-regulated in the five metastatic cell lines, while 24 genes (0.34%) were down-regulated in four of the metastatic cell lines. The usefulness of our system for the identification of genes associated with metastasis of mammary carcinoma is demonstrated by the identification of genes which have already been implicated in metastasis of mammary carcinoma. This suggests that further evaluation of identified de-regulated genes, which until now have not been seen in context with metastasis of mammary carcinoma, should be undertaken.

Transcriptional profiling of cell lines derived from an orthotopic pancreatic tumor model reveals metastasis-associated genes.

In order to identify genes associated with metastasis of ductal pancreatic adenocarcinoma we investigated pancreatic tumor cell lines derived from an orthotopic pancreatic tumor model in SCID mice. Transcriptional profiling (Affymetrix Gene Chip Technology) was performed with cell lines derived from the primary tumor and metastatic lesions such as mesentery, liver and lungs. We scored for genes commonly deregulated in the cell lines derived from the metastatic lesions. Of 7070 genes investigated, 59 (0.83%) were found to be deregulated in the cell lines derived from the metastatic lesions. We grouped these genes into different categories such as transcription, translation, cytoskeleton, cell adhesion, chromosome instability, tumor suppressor genes, enzymes and "others". The most remarkable features of the system are the up-regulation of high mobility group protein HMG-I (Y), twenty-one ribosomal proteins, GAPDH and the laminin receptor in the cell lines derived from the metastatic lesions, whereas tumor suppressor genes such as maspin and RB1 were down-regulated. Inhibition or reconstitution of the activity of these targets are an emerging strategy for inhibition of metastasis in this system.

Identification of THW, a putative new tumor suppressor gene.

Differential Display between metastasizing and non-metastasizing human melanoma cell lines NMCL-1 and 530 led to the identification of a putative transmembrane receptor, designated as THW, which is down-regulated in the metastasizing cell line. THW is composed of 193 aa, exhibits four putative transmembrane domains and does not reveal any homology to other proteins. Down-regulation of THW is correlated with metastatic capacity of melanoma cell lines. THW was down-regulated in mammary carcinoma cell lines compared with cell lines derived from non-malignant mammary epithelium, in pancreas cell lines derived from metastases compared with a cell line derived from a primary tumor and in several tumor tissues compared with normal tissues. The function of THW as a tumor suppressor is emphasized by the location of the THW gene on chromosome 6q. LOH for this region has been reported in malignant melanoma and prostate, pancreas, uterine and mammary carcinomas.