Myeloid cell production within the bone marrow is accelerated in the setting of cancer, and the numbers of circulating and infiltrating neutrophils and granulocytic myeloid derived suppressor cells (MDSCs) correlate with tumor progression and patient survival. Cancer is therefore able to hijack the normally host-protective immune system and use it to further fuel growth and metastasis. Myeloid cells secrete neutrophil elastase and neutrophil extracellular traps (NETs) in response to cues within the tumor microenvironment, thereby leading to enhanced activity in a variety of cancer types. Neutrophil elastase may indeed be a driver of tumorigenesis, since genetic deletion and pharmacological inhibition markedly reduces tumor burden and metastatic potential in numerous preclinical studies. In this review, we examine the current evidence for neutrophil elastase as a stimulatory factor in cancer, focusing on precise mechanisms by which it facilitates primary tumor growth and secondary organ metastasis. We conclude with a brief overview of neutrophil elastase inhibitors and discuss their potential use in cancer therapy.

Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer (PCa) and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here it is reported that granulocytic myeloid-derived suppressor cells (MDSCs) are the predominant tumor infiltrating cells in PCa xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their pro-tumorigenic actions in part through neutrophil elastase (ELA2/NE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in PCa xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated mitogen-activated protein kinase (MAPK) signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in PCa cells. Functionally, NE stimulated proliferation, migration, and invasion of PCa cells in vitro. Immunohistochemistry (IHC) on human PCa clinical biopsies revealed co-expression of NE and infiltrating CD33+ MDSCs.

Objective The regulation of vascular permeability, leukocyte trafficking, and the integrity of endothelial cell-cell contacts are closely linked by a complex mechanism of inter-regulation. Here we investigate the role of KRIT1, an adherens junction accessory protein required for cell-cell junction stability, in the regulating these vascular functions. Methods and Results Krit1+/− mice exhibited an enhanced edematous response to the complex inflammatory stimuli found in the passive K/BxN model of inflammatory arthritis and the murine air pouch model, yet leukocyte infiltration was unchanged. Correspondingly, reduced KRIT1 expression increased baseline arteriole and venule permeability 2-fold over that of wildtype littermates, as measured by intravital microscopy of the intact cremaster muscle vascular network, but this increase was not accompanied by increased leukocyte extravasation or activation. Direct stimulation with tumor necrosis factor–α induced increased permeability in wildtype mice, but surprisingly, no increase over baseline levels was observed in Krit1+/− mice, despite extensive leukocyte activation. Finally, adoptive transfer of Krit1+/− bone marrow failed to increase permeability in wildtype mice. However, reduced expression of KRIT1 in the hematopoietic lineage dampened the differences observed in baseline permeability. Conclusions Taken together, our data indicate an integral role for KRIT1 in microvessel homeostasis and the vascular response to inflammation.

Lymphangioleiomyomatosis (LAM) is a rare disease in women. Patients with LAM develop metastatic smooth-muscle cell adenomas within the lungs, resulting in reduced pulmonary function. LAM cells contain mutations in tuberous sclerosis genes (TSC1 or TSC2), leading to up-regulation of mTORC1 activity and elevated proliferation. The origin of LAM cells remains unknown; however, inactivation of Tsc2 gene in the mouse uterus resulted in myometrial tumors exhibiting LAM features, and approximately 50% of animals developed metastatic myometrial lung tumors. This suggests that LAM tumors might originate from the uterine myometrium, possibly explaining the overwhelming prevalence of LAM in female. Here, we demonstrate that mouse Tsc2-null myometrial tumors exhibit nearly all the features of LAM, including mTORC1/S6K activation, as well as expression of melanocytic markers and matrix metalloproteinases (MMPs). Estrogen ablation reduces S6K signaling and results in Tsc2-null myometrial tumor regression. Thus, even without TSC2, estradiol is required to maintain tumors and mTORC1/S6K signaling. Additionally, we find that MMP-2 and −9, as well as neutrophil elastase (NE), are overexpressed in Tsc2-null myometrial tumors in an estrogen-dependent fashion. In vivo fluorescent imaging using MMP- or NE-sensitive optical biomarkers confirms that protease activity is specific to myometrial tumors. Similar to LAM cells, uterine Tsc2-null myometrial cells also overexpress melanocytic markers in an estrogen-dependent fashion. Finally, we identify glycoprotein NMB (GPNMB) as a melanocytic marker up-regulated in Tsc2-null mouse uteri and human LAM samples. Our data highlight the potential importance of estradiol in LAM cells, suggesting that anti-estrogen therapy may be a treatment modality. Furthermore, proteases and GPNMB might be useful LAM biomarkers.