Antibody Diversity in Cancer: Translational Implications and Beyond.

Patients with cancer tend to develop antibodies to autologous proteins. This phenomenon has been observed across multiple cancer types, including bladder, lung, colon, prostate, and melanoma. These antibodies potentially arise due to induced inflammation or an increase in self-antigens. Studies focusing on antibody diversity are particularly attractive for their diagnostic value considering antibodies are present at an early diseased stage, serum samples are relatively easy to obtain, and the prevalence of antibodies is high even when the target antigen is minimally expressed. Conversely, the surveillance of serum proteins in cancer patients is relatively challenging because they often show variability in expression and are less abundant. Moreover, an antibody's presence is also useful as it suggests the relative immunogenicity of a given antigen. For these reasons, profiling antibodies' responses is actively considered to detect the spread of antigens following immunotherapy. The current review focuses on expanding the knowledge of antibodies and their diversity, and the impact of antibody diversity on cancer regression and progression.

Leptin secreted from testicular microenvironment modulates hedgehog signaling to augment the endogenous function of Leydig cells.

Although testosterone deficiency (TD) may be present in one out of five men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that the TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs, and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of the TME (Sertoli and PMC). The results demonstrated that TME secretes leptin, which induces LSC differentiation and increases testosterone production. Leptin's effects on LSC differentiation and testosterone production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin binds to the leptin receptor on LSCs and induces DHH signaling to modulate LSC differentiation. Leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effect on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.