NGAL as a Potential Target in Tumor Microenvironment

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.

Keywords: NGAL; SASP; iron; siderophores; tumor stroma.

Figure 1

NGAL in human diseases. Different pathologic conditions show a crucial involvement of NGAL: from the inflammatory response to the acute and chronic kidney injury as well to the cardiac and liver diseases (A). In particular, NGAL plays an important role in cancer given its ability to induce cell growth and to protect neoplastic cells from apoptosis, when complexed with iron (Fe), and to promote metastasis, when complexed with MMP-9 (B).

Figure 2

NGAL expression in etoposide-induced senescent cancer cell lines. Adapted from Cancer SENESCopedia (https://ccb.nki.nl/publications/cancer-senescence/, assessed on 10 November 2021).

Figure 3

Potential role for NGAL in modulation of iron homeostasis in senescent cells and iron-dependent control of their secretome.

Figure 4

NGAL skills in tumor microenvironment. Cancer cell-secreted NGAL binds extracellular iron (Fe) and promotes tumor mass proliferation and survival via autocrine fashion. NGAL/Fe autocrine stimulation also leads to cancer cells to secrete chemokines (CXCLn, CCLn) that induce macrophages chemoattraction in tumor microenvironment. Macrophages in turn produce additional NGAL to promote cancer cell growth, epithelial–mesenchymal transition (EMT) and endothelial trans-migration. NGAL is also released by fibroblasts and neutrophils to contribute to the metastatic spread of cancer cells given its ability to form a complex with MMP-9 released by stromal and neoplastic cells that enhances its enzymatic activity. In addition, neutrophils-secreted NGAL induces the mesenchymal-epithelial transition (MET) of cancer cells, a critical step for successful colonization of metastatic cells. Even if senescent cells also release NGAL in tumor microenvironment, no information is available about their contribution to the NGAL-mediated cancer progression.