Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

Plasminogen activators, tissue degradation, and cancer.

I. Introduction BASIC AND acidic fibroblast growth factors (FGFs) are closely related molecules that show a similar range of biological activities. They differ, however, in some of their physical and chemical properties and in their tissue distribution (1). Basic FGF [bFGF isoelectric point (pi) 9.6] was first identified by its ability to cause the proliferation and phenotypic transformation of BALB/c 3T3 fibroblasts (2, 3). Acidic FGF (aFGF, pi 5.6) was first identified by its ability to cause proliferation and delayed differentiation of myoblasts (4); it was later rediscovered on the basis of its ability to stimulate endothelial cell proliferation (5, 6). As expected from their structural relationship, both FGF and aFGF interact with the same receptor (7), thereby having similar, if not identical, properties. In contrast to aFGF, which has a cellular distribution more restricted than bFGF, many different cells synthesize bFGF, and essentially all have a specific high affinity receptor for this peptide. ...

Structural characterization and biological functions of fibroblast growth factor

Hepatic lipocytes were isolated from normal rat liver and established in culture. A virtually pure isolate was obtained by fractionating enzymatically digested liver on a discontinuous gradient of arabinogalactan. Isolated cells displayed prominent rough endoplasmic reticulum and typical cytoplasmic droplets containing vitamin A. Lipocytes in primary culture were shown by immunofluorescence to secrete collagen types I, III, and IV and also laminin. Immunoassay of culture media showed that lipocytes during the first week in culture secrete type I (72.1-86.2% of total measured soluble collagen), type III (2.6-7.2%), and type IV (11.2-29.7%) collagens. Five percent of total secreted protein was collagen compared with 0.2% in similarly cultured hepatocytes and 1.7% in sinusoidal endothelial cells, as measured by the production of peptide-bound [3H]hydroxyproline in cells incubated with [3H]proline. The calculated amount of collagen synthesized by lipocytes per microgram of cellular DNA was 10-fold greater than that produced by hepatocytes and over 20-fold greater than that produced by endothelial cells. The findings indicate that collagen synthesis and secretion are specialized functions of hepatic lipocytes, and that, in cells from normal liver, this represents production primarily of type I collagen. The phenotypic resemblance of these cells to fibroblasts supports the hypothesis that lipocytes are a major source of collagen in pathologic fibrosis and may be precursors of the fibroblast-like cells observed in liver injury.

https://www.pnas.org/content/pnas/82/24/8681.full.pdf

Hepatic lipocytes: the principal collagen-producing cells of normal rat liver

Fibroblast growth factor

Molecular and biological characterization of fibroblast growth factor, an angiogenic factor which also controls the proliferation and differentiation of mesoderm and neuroectoderm derived cells.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840020104

Collagen Production by Rat Hepatocytes and Sinusoidal Cells in Primary Monolayer Culture

Regulation of protein secretion in Chinese hamster ovary cells by cell cycle position and cell density. Plasminogen activator, procollagen fibronectin.

Vascular endothelial cells derived from adult bovine aortic arch can be grown in two ways, either in the presence or absence of fibroblast growth factor. The types of collagen produced by cultures under these two con- ditions have been compared. In the presence of fibroblast growth factor, cells grow in an orderly fashion, express their normal phenotype and synthesize primarily type III collagen plus collagens types IV and V at a ratio of 10: 1: 3. Cultures grown in the absence of the factor lose their orderly pattern of growth, lose polarity and normal phenotypic expression. They devote twice the proportion of total protein-synthesizing capacity to collagen, and now synthesize type I in addition to the other collagen types. The ratio of collagen types I: III: IV: V is approxi- mately 30:70:1:13. The kinds of type V collagen chains expressed are also altered. Fibroblast growth factor appears to modulate collagen synthesis, the major component of the extracellular matrix, and indirectly modulates the phenotypic expression of cultured vascular endothelial cells. In atherosclerosis, type I collagen is found in association with the intimal layer. The disorderly growth and the abnormal production of type I collagen by these vascular endothelial cells cultured in the absence of fibroblast growth factor is a model for a number of pathological situations including atherosclerotic plaque formation.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1982.tb05888.x

Scheffer C. G. Tseng

Papers

Collagen Production by Rat Hepatocytes and Sinusoidal Cells in Primary Monolayer Culture

Regulation of protein secretion in Chinese hamster ovary cells by cell cycle position and cell density. Plasminogen activator, procollagen fibronectin.

Fibroblast Growth Factor Modulates Synthesis of Collagen in Cultured Vascular Endothelial Cells

Types of Collagen Synthesized by Normal Rat Liver Hepatocytes in Primary Culture

A new rapid method for quantitating radioactive proline, 4-hydroxyproline, and 3-hydroxyproline