Mouse fibroblast activation protein: molecular cloning, alternative splicing and expression in the reactive stroma of epithelial cancers.
The growth of solid neoplasms requires the recruitment of a supporting stroma. In most epithelial cancers, this stromal compartment comprises newly formed blood vessels and abundant, reactive stromal fibroblasts. Tumor stromal fibroblasts are not transformed but differ from resting fibrocytes in normal adult tissues by an altered pattern of gene expression. In human cancers, this includes induction of the cell-surface-bound fibroblast-activation protein (FAP), a member of the serine protease family encoded by the FAP gene on chromosome 2. In this study, we have cloned a complementary DNA for Fap, the murine homologue of FAP. The predicted murine FAP protein, mFAP, shares 89% amino-acid-sequence identity with human FAP, including a perfectly conserved catalytic triad. Cultured mouse embryo fibroblasts and mouse embryonic tissues were found to express Fap transcripts. In addition, the host-derived, fibroblast-rich stroma of human epithelial-cancer xenografts grown in immunodeficient mice also expresses Fap. Sequencing of reverse-transcription-PCR products indicates that 3 distinct Fap splice variants can be detected in tissues. Our findings suggest a close similarity in structure and tissue expression of FAP in different species. By extending the analysis of FAP to the mouse, new in vivo test systems become available for genetic and therapeutic manipulations and for the study of FAP regulation and function in embryonic development and in epithelial cancers.
Niedermeyer
J
J
Oncology Research Group, Dr. Karl Thomae GmbH/Boehringer Ingelheim Pharma, Biberach, Germany.
Scanlan
M J
MJ
Garin-Chesa
P
P
Daiber
C
C
Fiebig
H H
HH
Old
L J
LJ
Rettig
W J
WJ
Schnapp
A
A
D000230:Adenocarcinoma / Q000473:pathology; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm; D001483:Base Sequence; D014408:Biomarkers, Tumor; D002460:Cell Line; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D003001:Cloning, Molecular; D010450:Endopeptidases; D004848:Epithelium; D018093:Gelatinases; D006133:Growth Substances / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007739:L Cells; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009838:Oligodeoxyribonucleotides; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000099167:Fibroblast Activation Protein Alpha
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D006133:Growth Substances; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha