A prototypic matricellular protein in the tumor microenvironment--where there's SPARC, there's fire

Within the tumor microenvironment is a dynamic exchange between cancer cells and their surrounding stroma. This complex biologic system requires carefully designed models to understand the role of its stromal components in carcinogenesis, tumor progression, invasion, and metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a prototypic matricellular protein at the center of this exchange. Two decades of basic science research combined with recent whole genome analyses indicate that SPARC is an important player in vertebrate evolution, normal development, and maintenance of normal tissue homeostasis. Therefore, SPARC might also play an important role in the tumor microenvironment. Clinical evidence indicates that SPARC expression correlates with tumor progression, but tightly controlled animal models have shown that the role of SPARC in tumor progression is dependent on tissue and tumor cell type. In this Prospectus, we review the current understanding of SPARC in the tumor microenvironment and discuss current and future investigations of SPARC and tumor-stromal interactions that require careful consideration of growth factors, cytokines, proteinases, and angiotropic factors that might influence SPARC activity and tumor progression.     

Adaptive radiations: there's something about finches

A phylogenetic tree for the extant Hawaiian honeycreepers charts their diversification over the past 6 million years.     

Chimpanzee behavior: there's no place like home

During times of crisis, humans often seek the comforts of home. New observations indicate that, during periods of food shortage, male chimpanzees behave in similar fashion by returning to the areas they occupied with their mothers in youth.     

Applying for grant funds: there's help around the corner

Scientists should know where to get help when they write grant proposals. Books, videos, consultants and colleagues can all be useful. The World Wide Web is an excellent resource for finding competitors, collaborators and a wealth of other useful information such as funding agencies, available grant money, pertinent articles and form pages for grant applications. Software is available to help you make an outline of your proposal, prepare the required figures and tables and build a database of references from which to create a bibliography. This article will point you in the right direction for a plethora of information and resources.     

Ay, there's the Rab: organelle maturation by Rab conversion

Is endocytosed cargo transported by vesicular intermediates between early and late endosomes, or does an endosome mature while its cargo remains in place? Current work suggests that the latter takes place within the endosomal system via a process termed Rab conversion.     

The obstetrical dilemma hypothesis: there's life in the old dog yet

The term ‘obstetrical dilemma’ was coined by Washburn in 1960 to describe the trade-off between selection for a larger birth canal, permitting successful passage of a big-brained human neonate, and the smaller pelvic dimensions required for bipedal locomotion. His suggested solution to these antagonistic pressures was to give birth prematurely, explaining the unusual degree of neurological and physical immaturity, or secondary altriciality, observed in human infants. This proposed trade-off has traditionally been offered as the predominant evolutionary explanation for why human childbirth is so challenging, and inherently risky, compared to that of other primates. This perceived difficulty is likely due to the tight fit of fetal to maternal pelvic dimensions along with the convoluted shape of the birth canal and a comparatively low degree of ligamentous flexibility. Although the ideas combined under the obstetrical dilemma hypothesis originated almost a century ago, they have received renewed attention and empirical scrutiny in the last decade, with some researchers advocating complete rejection of the hypothesis and its assumptions. However, the hypothesis is complex because it presently captures several, mutually non-exclusive ideas: (i) there is an evolutionary trade-off resulting from opposing selection pressures on the pelvis; (ii) selection favouring a narrow pelvis specifically derives from bipedalism; (iii) human neonates are secondarily altricial because they are born relatively immature to ensure that they fit through the maternal bony pelvis; (iv) as a corollary to the asymmetric selection pressure for a spacious birth canal in females, humans evolved pronounced sexual dimorphism of pelvic shape. Recently, the hypothesis has been challenged on both empirical and theoretical grounds. Here, we appraise the original ideas captured under the ‘obstetrical dilemma’ and their subsequent evolution. We also evaluate complementary and alternative explanations for a tight fetopelvic fit and obstructed labour, including ecological factors related to nutrition and thermoregulation, constraints imposed by the stability of the pelvic floor or by maternal and fetal metabolism, the energetics of bipedalism, and variability in pelvic shape. This reveals that human childbirth is affected by a complex combination of evolutionary, ecological, and biocultural factors, which variably constrain maternal pelvic form and fetal growth. Our review demonstrates that it is unwarranted to reject the obstetrical dilemma hypothesis entirely because several of its fundamental assumptions have not been successfully discounted despite claims to the contrary. As such, the obstetrical dilemma remains a tenable hypothesis that can be used productively to guide evolutionary research.     

Cathepsin D deficiency and NCL/Batten disease: there's more to death than apoptosis

Animal models of cathepsin D (CD) deficiency are characterized by a progressive and relentless neurodegenerative phenotype similar to that observed in Neuronal Ceroid Lipofuscinoses (NCL), a group of pediatric neurodegenerative diseases known collectively as Batten Disease. We have shown recently that the targeted deletion of the pro-apoptotic molecule Bax prevents apoptotic markers but not neuron death and neurodegeneration induced by CD deficiency, which suggests that alterations in the macroautophagy-lysosomal degradation pathway can mediate neuron death in NCL/Batten Disease in the absence of apoptosis. Herein, we review CD deficiency in the broader context of NCL and offer potential mechanisms for neuron death and neurodegeneration induced by CD deficiency.     

Behind every smile there's teeth: Cathepsin B's function in health and disease with a kidney view

Cathepsin B (CatB) is a very abundant lysosomal protease with endo- and carboxydipeptidase activities and even ligase features. In this review, we will provide a general characterization of CatB and describe structure, structure-derived properties and location-dependent proteolytic actions. We depict CatB action within lysosome and its important roles in lysosomal biogenesis, lysosomal homeostasis and autophagy rendering this protease a key player in orchestrating lysosomal functions. Lysosomal leakage and subsequent escape of CatB into the cytosol lead to harmful actions, e.g. the role in activating the NLPR3 inflammasome, affecting immune responses and cell death. The second focus of this review addresses CatB functions in the kidney, i.e. the glomerulus, the proximal tubule and collecting duct with strong emphasis of its role in pathology of the respective segment. Finally, observations regarding CatB functions that need to be considered in cell culture will be discussed. In conclusion, CatB a physiologically important molecule may, upon aberrant expression in different cellular context, become a harmful player effectively showing its teeth behind its smile.