Mini-reviewLipocalin 2 in cancer: When good immunity goes bad
Introduction
Lipocalin 2 (LCN2) or Neutrophil Gelatinase Associated Lipocalin (NGAL) or siderocalin, is a dynamic 25 kDa protein with roles in innate immunity and in a variety of pathologies. Its murine ortholog, 24p3, was first identified to be upregulated in SV40-infected primary mouse kidney cell cultures [1], and since then, this unique molecule has evolved into a target of interest amongst immunologists, developmental biologists, and cancer biologists.
LCN2 is part of a larger family of proteins known as lipocalins. Structurally, lipocalins are highly conserved, small molecules whose key structural feature is a β-barrel composed of eight anti-parallel strands [2]. This central cavity of a lipocalin molecule permits binding to small, hydrophobic molecules including retinoids, hormones, and fatty acids [2]. The potential of transporting a range of small molecules via specific cell-surface receptors defines the family and allows LCN2 biological functionality in various tissues [3].
Lipocalin 2 was initially defined as a powerful bacteriostatic agent active against various Gram-negative microorganisms through impeding bacterial iron sequestration [4]. Unexpectedly, however, LCN2 has been identified as a stress protein that is released in a variety of other sterile inflammatory conditions such as adipose obesity-related inflammation [5] and cancer.
LCN2 is over-expressed in many types of non-microbially-associated cancers including breast, pancreatic, and ovarian carcinomas [6]. Functionally, Lipocalin 2 has been shown to have roles in promoting tumorigenesis through enhancing tumor cell survival and proliferation, and metastatic potential. Of critical importance, blocking this molecule’s expression in several types of cancer delays or even abrogates tumorigenesis [7], [8], [9].
While its role in antibacterial immunity is well-characterized, the function of LCN2 in tumorigenesis is still poorly understood. Both the mechanism of its over-expression in cancers of diverse histological origin and its function in promoting tumor growth remain to be fully elucidated. We will discuss evidence suggesting that Lipocalin 2 serves two primary tumorigenic functions: (a) induction of the epithelial to mesenchymal transition (EMT) to promote metastasis, in part through its stabilization of matrix metalloproteinase 9 (MMP-9), and (b) promotion of tumor cell survival through iron scavenging. We will also discuss new evidence suggesting that LCN2 over-expression in tumors may result from stimuli present in the tumor microenvironment, including hypoxia and inflammation. Recent findings suggest that the tumor endoplasmic reticulum (ER) stress response, which is triggered by these microenvironmental noxae, mediates LCN2 production.
Section snippets
Lipocalin 2 and innate immunity
In humans, LCN2 was originally found in granules of neutrophils, hence its name NGAL [10]. Since its identification, it has been established that the primary role of Lipocalin 2 in innate immunity is to counteract bacterial iron scavenging by blocking bacterial trafficking of iron.
Kjeldsen et al. [10] first purified LCN2 from the matrix of neutrophils and suggested its immune role by demonstrating that neutrophils stimulated with bacterial secretagogues upregulate LCN2 in a similar manner as
Lipocalin 2 in cancer
Recent evidence points to a role of LCN2 in facilitating tumorigenesis in various tissues. An analysis using the NCI’s Cancer Genome Anatomy Project’s Serial Analysis of Gene Expression (SAGE) Anatomic Viewer reveals that LCN2 is over-expressed in several human carcinomas (lung, stomach, pancreas and liver) relative to their normal tissue counterparts (Fig. 1). These results support prior evidence that LCN2 is upregulated in various epithelial cancers.
The dual functions of Lipocalin 2 in cancer
One similarity between bacterial infection and tumorigenesis is the battle over limited resources: bacteria oppose the innate immune system for metabolites, including iron, and rapidly dividing cancer cells continually consume nutrients (including iron) in a microenvironment with scarce vasculature. It is known that Lipocalin 2 contains bacterial infection by reducing iron availability, but a role for Lipocalin 2 in cancer iron metabolism remains to be fully investigated. Presently, two
Tumor microenvironmental stimuli induce LCN2
Despite the increasing number of reports demonstrating LCN2’s upregulation and function in cancer, what drives LCN2 over-expression in tumors is less understood. Here, we discuss evidence which suggest that stimuli present in the tumor microenvironment cause LCN2 expression.
The ER stress response at the interface of tumor microenvironmental noxae and LCN2 expression
The tumor microenvironment contains nutrients and oxygen in limited supply. Resultant stress signals converge upon the endoplasmic reticulum, eliciting the adaptive unfolded protein response (UPR), a survival pathway that has been shown to be critical in facilitating tumorigenesis (reviewed in [76]). The role of hypoxia in inducing an UPR in tumor cells has been analyzed in detail (reviewed in [77]), and hypoxia in the microenvironment of spontaneously-growing tumors in mice was found to elicit
Conclusions
Lipocalin 2 is a versatile molecule with an apparent dual role: a beneficial one in innate immunity that protects against bacterial pathogens, and a detrimental one when co-opted by cancer cells into a tumor-promoting role. Therefore, LCN2 belongs to a unique class of molecules with both immune and oncogenic properties. The aberrant expression of LCN2 in solid tumors is likely the response of cancer cells to hypoxia and pro-inflammation, microenvironmental noxae that both elicit the ER stress
Acknowledgments
The authors are thankful to Drs. Stephen Howell, Kary Mullis, Victor Nizet, and Sanford Shattil for insightful comments and suggestions. This work was supported in part by a Grant from the UCSD Academic Senate to M.Z. J.J.R. acknowledges support from the Frank H. and Eva B. Buck Foundation and the UCSD IMSD program, funded by NIH R25 Grant GM083275. N.R.M. acknowledges support from the UCSD Medical Scientist Training Program and NIDA T32 Training Grant DA007315-07A2.
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