Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg–Gly–Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.     

Cabinet of Curiosities: Venom Systems and Their Ecological Function in Mammals,with a Focus on Primates

Venom delivery systems (VDS) are common in the animal kingdom, but rare amongst mammals. New definitions of venom allow us to reconsider its diversity amongst mammals by reviewing the VDS of Chiroptera, Eulipotyphla, Monotremata, and Primates. All orders use modified anterior dentition as the venom delivery apparatus, except Monotremata, which possesses a crural system. The venom gland in most taxa is a modified submaxillary salivary gland. In Primates, the saliva is activated when combined with brachial gland exudate. In Monotremata, the crural spur contains the venom duct. Venom functions include feeding, intraspecific competition, anti-predator defense and parasite defense. Including mammals in discussion of venom evolution could prove vital in our understanding protein functioning in mammals and provide a new avenue for biomedical and therapeutic applications and drug discovery.     

Generic Anti-PEG Antibody Assay on ProterixBio’s (Formerly BioScale) ViBE Platform Shows Poor Reproducibility

PEGylation is a modification commonly used to increase the half-life of therapeutic proteins. The strategy for immunogenicity testing of these compounds should include methods to detect both anti-protein and anti-PEG antibodies. We previously reported a method for the detection of anti-PEG antibodies using ProterixBio’s (formerly BioScale) acoustic membrane microparticle (AMMP) technology. Our initial method development work showed the assay was capable of detecting antibodies in human serum with a sensitivity of 1 μg/mL with good reproducibility (CV?<?7%). Since the publication of this initial paper, additional experimentation was performed in an effort to validate the assay for support of clinical sample analysis. This additional data indicate that the method has high variability (CV%?>?20) and is unsuitable to support clinical sample analysis.     

Folliculotropism in pigmented facial macules: Differential diagnosis with reflectance confocal microscopy

Pigmented facial macules are common on sun damage skin. The diagnosis of early stage lentigo maligna (LM) and lentigo maligna melanoma (LMM) is challenging. Reflectance confocal microscopy (RCM) has been proven to increase diagnostic accuracy of facial lesions. A total of 154 pigmented facial macules, retrospectively collected, were evaluated for the presence of already‐described RCM features and new parameters depicting aspects of the follicle. Melanocytic nests, roundish pagetoid cells, follicular infiltration, bulgings from the follicles and many bright dendrites and infiltration of the hair follicle (ie, folliculotropism) were found to be indicative of LM/LMM compared to non‐melanocytic skin neoplasms (NMSNs), with an overall sensitivity of 96% and specificity of 83%. Concerning NMSNs, solar lentigo and lichen planus‐like keratosis resulted better distinguishable from LM/LMM because usually lacking malignant features and presenting characteristic diagnostic parameters, such as epidermal cobblestone pattern and polycyclic papillary contours. On the other hand, distinction of pigmented actinic keratosis (PAK) resulted more difficult, and needing evaluation of hair follicle infiltration and bulging structures, due to the frequent observation of few bright dendrites in the epidermis, but predominantly not infiltrating the hair follicle (estimated specificity for PAK 53%). A detailed evaluation of the components of the folliculotropism may help to improve the diagnostic accuracy. The classification of the type, distribution and amount of cells, and the presence of bulging around the follicles seem to represent important tools for the differentiation between PAK and LM/LMM at RCM analysis.