The most common human cancers --lung, breast and prostate -- have a great avidity for bone, leading to painful and untreatable consequences. What makes some cancers, but not others, metastasize to bone, and how do they alter its physiology? Some of the molecular mechanisms that are responsible have recently been identified, and provide new molecular targets for drug development.

http://helsenet.info/pdf/metastasis/1.pdf

Metastasis to bone: causes, consequences and therapeutic opportunities

The lipocalin protein family is a large group of small extracellular proteins. The family demonstrates great diversity at the sequence level; however, most lipocalins share three characteristic conserved sequence motifs, the kernel lipocalins, while a group of more divergent family members, the outlier lipocalins, share only one. Belying this sequence dissimilarity, lipocalin crystal structures are highly conserved and comprise a single eight-stranded continuously hydrogen-bonded antiparallel beta-barrel, which encloses an internal ligand-binding site. Together with two other families of ligand-binding proteins, the fatty-acid-binding proteins (FABPs) and the avidins, the lipocalins form part of an overall structural superfamily: the calycins. Members of the lipocalin family are characterized by several common molecular-recognition properties: the ability to bind a range of small hydrophobic molecules, binding to specific cell-surface receptors and the formation of complexes with soluble macromolecules. The varied biological functions of the lipocalins are mediated by one or more of these properties. In the past, the lipocalins have been classified as transport proteins; however, it is now clear that the lipocalins exhibit great functional diversity, with roles in retinol transport, invertebrate cryptic coloration, olfaction and pheromone transport, and prostaglandin synthesis. The lipocalins have also been implicated in the regulation of cell homoeostasis and the modulation of the immune response, and, as carrier proteins, to act in the general clearance of endogenous and exogenous compounds.

/pdf/the-lipocalin-protein-family-structure-and-function-lbmezfltm1.pdf

The lipocalin protein family: structure and function

Publisher Summary The fibroblast growth factors (FGFs) constitute a family of closely related polypeptide mitogens There are seven members of this family, identified on the basis of amino acid sequence homologies The FGF family has distinguished itself from other growth factor families by virtue of the pleiotropic actions of its members This chapter discusses the structural and functional diversity in the FGF receptor multigene family The effects of FGFs are known to be mediated by high-affinity receptor tyrosine kinases The structurally diverse receptor molecules are also functionally different The characterization of structural and functional diversity within the FGF receptor shows the differences in the mechanisms of action among members of the FGF family The first members of the FGF family to be purified and characterized were acidic FGF (aFGF) and basic FGF (bFGF), which are purified on the basis of their mitogenicity toward fibroblasts by using bovine pituitary Functional differences among the different receptor forms are observed in the chapter at two levels The long-range goal of designing the effective agonist and antagonists of FGF action has considerable therapeutic value

Structural and Functional Diversity in the FGf Receptor Multigene Family

Fibroblast growth factor

Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.20408

Human prostate cancer risk factors.

To find candidates for the mediator of the growth-promoting action of androgen in rat prostates, the changes in the steady-state levels of mRNAs coding for several growth factors and their receptors were examined by Northern blot analysis during castration-induced involution, and subsequent regrowth induced by androgen in the ventral and dorsolateral lobes. The changes in the growth factor systems and a typical secretory protein in the ventral lobe were similar to, but more prominent than, those in the dorsolateral lobe, showing the higher androgen dependency of the ventral lobe. Among the growth factors and their receptors investigated, only epidermal growth factor (EGF) showed apparent positive androgen dependency: EGF mRNA content in the ventral lobe decreased to about 30% of the normal level within 24 hr after castration, and increased, attaining about 200–300% of the normal level 3–5 days after androgen administration to castrated rats. mRNAs coding for all other factors examined, i.e., transforming growth factor-α (TGF-α), EGF receptor, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), FGF receptor 1, TGF-β1, TGF-β type II receptor, hepatocyte growth factor (HGF), and c-MET/HGF receptor, increased after castration in greater or lesser degree, and after a brief pause or a decrease some of them increased again attaining a second peak 3–5 days after androgen replacement. The second increase was evident in TGF-α, EGF receptor, KGF, and c-MET mRNAs. These results indicate the possibility that multiple growth factor-receptor systems participate in the androgen-dependent regrowth of castrated rat prostates. © 1996 Wiley-Liss, Inc.

Changes in gene expression of growth factors and their receptors during castration-induced involution and androgen-induced regrowth of rat prostates

Probasin, a rat prostatic protein, is statistically related to members of a protein family that includes serum, cellular, and nuclear proteins. In vivo, probasin appears both in the secretions and in the nucleus of prostatic epithelial cells. Using primer extension and S1 nuclease protection assays we detected only one probasin mRNA. Thus, the localization of this protein to two separate cellular regions must be encoded by this one mRNA. Furthermore, in vitro translation of synthetic probasin mRNA demonstrated that a protein containing a signal peptide and a protein lacking a signal peptide were synthesized by initiation at different AUG codons. These data are consistent with a mechanism of translational regulation of a eukaryotic bifunctional mRNA.

Regulation of a bifunctional mRNA results in synthesis of secreted and nuclear probasin.

The rat prostate contains two types of growth factors capable of stimulating DNA synthesis in BALB/3T3 cells. These rat prostatic growth factors (RPGF) were separable by a different affinity for heparin: low affinity type RPGF and high affinity (HiA) type RPGF. About 80% of the RPGF in the cytosol from normal prostates was low affinity type, whereas more than 80% in the cytosol from the Dunning tumors was HiA type. Elution profile of HiA-RPGF showed two peaks of activity eluted from the heparin-Sepharose column, one at 1.3-1.4 M NaCl (HiA1-RPGF) and the other at 1.6-1.7 M NaCl (HiA2-RPGF). HiA2-RPGF could be purified 1100-fold from the Dunning tumor (AT-3 subline) in about 20% recovery by heparin-Sepharose chromatography. The partially purified HiA2-RPGF in the Dunning tumor has a molecular weight of about 19,000 and isoelectric point of about 3.8, and stimulated DNA synthesis at a concentration of about 0.25 nM. The activity was lost by heat treatment at 70 degrees C for 5 min and by acid treatment, whereas it was stimulated by incubating with dithiothreitol. The HiA2-RPGF did not have transforming growth factor activity at a concentration of 250 ng/ml or lower in the presence of epidermal growth factor.

Heparin binding affinity of rat prostatic growth factor in normal and cancerous prostates: partial purification and characterization of rat prostatic growth factor in the Dunning tumor.

A human prostatic growth factor (hPGF): partial purification and characterization.

Primary cultured epithelial cells derived from the rat dorsolateral prostate proliferated in serum-free nutrient medium WAJC 404 supplemented with mitogens: insulin (650 nM), cholera toxin (120 pM), epidermal growth factor (EGF) (2.5 nM), dexamethasone (300 nM), and bovine pituitary extract (25 micrograms/ml). The culture consisted of two types of epithelial cell colonies: one originated from single cells or small cell aggregates and the other was epithelial cell outgrowth from small tissue fragments attached to a substratum. There were differences in requirements for the mitogens between the two types of colonies. Requirements for cholera toxin, bovine pituitary extract, and dexamethasone were higher in the former type of colonies, and those for EGF were higher in the latter type of colonies. Proliferation of the epithelial cells in either type of colony was suppressed more than 50% by 1 nM dihydrotestosterone. This suppressive effect was not mediated by stromal component in the tissue fragments, and was counteracted by cyproterone acetate, indicating specific and direct action of the androgen on prostate epithelial cells. The results suggest that there is discrete participation of polypeptide growth factors and androgen in proliferation and differentiation, respectively, of prostate epithelial cells in vivo.

Nozomu Nishi

Papers

Changes in gene expression of growth factors and their receptors during castration-induced involution and androgen-induced regrowth of rat prostates

Regulation of a bifunctional mRNA results in synthesis of secreted and nuclear probasin.

Heparin binding affinity of rat prostatic growth factor in normal and cancerous prostates: partial purification and characterization of rat prostatic growth factor in the Dunning tumor.

A human prostatic growth factor (hPGF): partial purification and characterization.

Proliferation of epithelial cells derived from rat dorsolateral prostate in serum-free primary cell culture and their response to androgen.