PRL-3 expression in metastatic cancers.
OBJECTIVE
Expression of the PRL-3 tyrosine phosphatase is elevated in liver metastases derived from colorectal cancer (CRC). We sought to determine the cellular basis of this elevation and assess the expression of PRL-3 in metastatic lesions derived from cancers of the colon and other tissues.


METHODS
We developed modifications of in situ hybridization methods that facilitated the study of paraffin-embedded sections. We also evaluated PRL-3 gene copy numbers using fluorescence in situ hybridization and developed antibodies to assess PRL-3 subcellular localization.


RESULTS
PRL-3 mRNA expression was elevated in nearly all metastatic lesions derived from CRCs, regardless of the site of metastasis (liver, lung, brain, or ovary). Expression was found in neoplastic cells, although tumor endothelium also expressed the gene. In contrast, little or no PRL-3 expression was observed in normal colon, nonmetastatic primary cancers, or metastatic lesions derived from cancers other than those of the colon (pancreas, stomach, or esophagus). Interphase fluorescence in situ hybridization confirmed that gene amplification was not the major cause of PRL-3 overexpression. Immunohistochemical analysis with anti-PRL-3 antibodies showed a cell membrane localization, consistent with the predicted isoprenylation of the protein.


CONCLUSIONS
These studies establish an unexpected and unprecedented specificity in metastatic gene expression profiles: PRL-3 is apparently expressed in CRC metastases to any organ but is not expressed in metastases of other cancers to the same organs or in nonmetastatic CRCs. PRL-3 is also expressed in tumor vasculature, regardless of the tumor source. These data raise intriguing questions about the role of protein phosphorylation in angiogenesis and cell-type-specific metastatic processes.
Bardelli
Alberto
A
The Howard Hughes Medical Institute University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio, USA.
Saha
Saurabh
S
Sager
Jason A
JA
Romans
Kathy E
KE
Xin
Baozhong
B
Markowitz
Sanford D
SD
Lengauer
Christoph
C
Velculescu
Victor E
VE
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
D001483:Base Sequence; D045744:Cell Line, Tumor; D003106:Colon / Q000201:enzymology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017931:DNA Primers; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D007413:Intestinal Mucosa / Q000201:enzymology; D009362:Neoplasm Metastasis / Q000235:genetics; D009363:Neoplasm Proteins; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
D017931:DNA Primers; D017874:Immediate-Early Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases