In Response: Murine proteolysis-inducing factor (PIF) is composed of a short peptide core with extensive N- and O-linked oligosaccharide chains. A human homologue of PIF has proved elusive, using approaches based on the structure of murine PIF. As for a human variant of the core peptide, the absence of a motif for glycosylation (1, 2) remains the most important barrier to accepting the notion that human cancer cells transform the dermcidin gene product into a PIF. As for the carbohydrate moieties that confer the proteolysis-inducing activity, the only means available for their identification or purification, a monoclonal antibody, is not a valid tool in human studies owing to extensive nonspecific binding (2). This fact is now acknowledged by M. Tisdale, and draws into question prior PIF immunoblot results in human subjects (3–5).
M. Tisdale provides no new insight about how human PIF could be revealed, if it were present. The suggestion that PIF can be verified by colocalization of reactions with antibodies to the core protein and carbohydrate is not useful because no antibody is specific for the critical carbohydrate part. Investigations of the putative human PIF have eluded efforts to find evidence of colocalization, in human-derived materials, of the peptide core, the oligosaccharide chains, and the proteolysis-inducing activity. The human core peptide is not glycosylated by human tumor cells and its presence in tumor cells bears no relationship to a cachexia phenotype (1, 2, 6). Similarly, a positive reaction with the antibody to the carbohydrate chain does not relate to either cachexia or malignant disease in humans (2–5) and none of the proteins reacting with this antibody are associated with a peptide of the sequence described for the core protein (2).
Human PIF is a molecule reported, to date, exclusively by a single laboratory, and this is the greatest limitation for the interest of PIF for our understanding of cancer cachexia. M. Tisdale could greatly clarify this research domain by disseminating to independent laboratories authentic human PIF with the structural and biological features claimed.