NGAL as a Potential Target in Tumor Microenvironment.

Elvira Crescenzi,Francesco Pacifico,Antonio Leonardi

doi:10.3390/ijms222212333

Abstract

The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling has been producing exciting results in cancer therapy: just think of anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies that, acting as immune checkpoint inhibitors, interrupt the inhibitory signaling exerted by cancer cells on immune cells or the CAR-T technology that fosters the reactivation of anti-tumoral immunity in a restricted group of leukemias and lymphomas. Nevertheless, many types of cancers, in particular solid tumors, are still refractory to these treatments, so the identification of novel molecular targets in tumor secretome would benefit from implementation of current anti-cancer therapeutical strategies. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein abundantly expressed in the secretome of various human tumors. It represents a promising target for the multiple roles that are played inside cancer and stromal cells, and also overall in their cross-talk. The review focuses on the different roles of NGAL in tumor microenvironment and in cancer senescence-associated secretory phenotype (SASP), highlighting the most crucial functions that could be eventually targetable in cancer therapy.

Highlights

Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein and, as such, is a strong candidate to play crucial roles in tumor microenvironment given that it is released by cancer cells, and by several non-neoplastic cell populations that contribute at different levels to cancer development and progression
These findings were further extended by Malone and coworkers who analyzed the impact of NGAL activity on proliferation and migration of triple negative breast cancer (TNBC) cell lines induced by conditioned media from TNBC-associated stromal cells
The multiple roles played by NGAL in tumor microenvironment make it a promising target for novel strategies of cancer therapy

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Several studies have shown that while the infiltration of CD8+ T lymphocytes and M1 polarized macrophages is associated with a favorable outcome given their tumor suppressor activities, the presence of Treg lymphocytes and M2 polarized tumor-associated macrophages (TAMs) in tumor stroma suggests a less favorable prognosis because they may directly stimulate tumor growth and progression [3] In addition to these well-known cell populations that durably reside in tumor microenvironment, senescent cells play an important role in shaping tumor stroma properties by virtue of their ability to secrete a number of factors which can have both beneficial and detrimental effects [1,3]. All the results mentioned above underscore the complex role of NGAL in different aspects of cell physiology and its contribution to a number of human pathologies including cancer

NGAL and Tumor Microenvironment

NGAL and the SASP

Targeting NGAL in Tumor Microenvironment

Conclusions