PerspectiveCANCER

How neutrophils promote metastasis

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Science  08 Apr 2016:
Vol. 352, Issue 6282, pp. 145-146
DOI: 10.1126/science.aaf7300

Metastatic disease is the main cause of death in cancer patients. Despite its devastating effects, the complex processes that lead to metastasis are poorly understood. During their journey to distant organs, cancer cells encounter various types of normal cells, including immune cells. Neutrophils are the most abundant immune cells in our blood, and they protect us from infections and facilitate wound healing. Intriguingly, neutrophils frequently accumulate in cancer patients. Recent studies have addressed the causal link between neutrophils and cancer in mouse tumor models, and point to a key role of neutrophils in promoting the most deadly aspect of cancer—its dissemination to distant organs (14).

Observations in cancer patients have linked elevated neutrophil counts in blood with increased risk for metastasis (5). Furthermore, ulceration of melanomas and subsequent neutrophilic inflammation are associated with invasiveness and a high probability for metastatic dissemination (1). Notably, a gene expression meta-analysis of ~18,000 human tumors across 39 cancer types linked an intratumoral neutrophil-related gene signature with poor prognosis (6). Are tumor-associated neutrophils just innocent bystanders that accumulate in aggressive tumors, or do they actually influence cancer behavior?

In two independent transgenic mouse models that mimic human breast cancer, primary breast tumors induce neutrophil accumulation in distant organs before the arrival of cancer cells, where they enhance the early steps of metastasis formation (2, 4). In one model, neutrophils localize to the lung where they produce leukotrienes that facilitate colonization by selectively propagating cancer cells with higher tumorigenic potential (4). In the other breast cancer mouse model, neutrophils promote lung metastasis by dampening antitumor T cell immunity (2). In both studies, neutrophil accumulation in the (pre)metastatic niche was initiated by signals emanating from the primary tumor.

Environmental stimuli can also trigger the prometastatic functions of neutrophils (1, 3). In a transgenic mouse model of melanoma, ultraviolet irradiation induced neutrophil activation in the skin, which promoted invasive and migratory behavior of melanoma cells, resulting in their expansion along blood vessel endothelial surfaces and distant metastasis formation (1). Additionally, bacterial lipopolysaccharideinduced acute lung inflammation initiated recruitment of neutrophils, which release proteases that can degrade thrombospondin-1, a matrix glycoprotein. Thrombospondin-1 inhibits tumorigenesis; thus, its destruction enhances metastatic outgrowth (3). Taken together, neutrophils can exert prometastatic functions in response to an inflammatory trigger from either the primary tumor or an environmental stimulus.

These experimental and clinical findings provide a scientific basis for therapeutically targeting the prometastatic role of neutrophils in cancer (see the figure). Importantly, such approaches must be developed with caution because neutrophils also exert antimetastatic activity in other experimental mouse models (7, 8). The ability to inhibit or promote tumor growth and metastatic spread of cancer cells in different experimental systems illustrates the context dependency and plasticity of the neutrophil phenotype. It is generally believed that progressively growing tumors perturb the process of granulopoiesis in the bone marrow, and switch neutrophils from tumorprotective to disease-promoting, moreimmature phenotypes (9). The molecular and cellular mechanisms orchestrating this phenomenon are only partially understood and represent a key challenge for current research. So far, it has become clear that molecules such as high mobility group box 1 (HMGB1) (1), interleukin-17 (IL-17) (2), and granulocyte colony-stimulating factor (G-CSF) (2, 10) promote the emergence of protumorigenic neutrophil phenotypes. Most likely, the genetic makeup and type of tumor are key determinants dictating the amount of these and other neutrophil-educating mediators that are produced.

Prometastatic neutrophils.

Molecules emerging from primary tumors or inflamed tissues can promote the emergence of protumorigenic neutrophils from the bone marrow. Neutrophils can facilitate metastasis through multiple mechanisms, such as the release of proteases that degrade antitumor factors, and leukotrienes that propagate metastasis-initiating cells (MIC). Protumorigenic neutrophils also can stimulate cancer cell expansion along blood vessel endothelial surfaces (not shown) and suppress antitumor T cell responses. Several neutrophiltargeting approaches could potentially inhibit metastasis, as shown. iNOS, inducible nitric oxide synthase.

ILLUSTRATION: K. SUTLIFF/SCIENCE

The selective interference with prometastatic neutrophil functions represents an attractive new strategy for cancer treatment. For example, an inhibitor of the arachidonate 5-lipoxygenase (the enzyme that transforms essential fatty acids into leukotrienes, which promote inflammation) impairs the formation of lung metastases (4). Lung metastases also can be inhibited by targeting neutrophil proteases (3). Interference with systemic inflammatory mediators that promote the emergence of prometastatic neutrophil phenotypes, such as IL-17 and G-CSF, represent an alternative treatment approach (2). Along the same lines, pharmacological blockade of endogenous innate immune-activating molecules such as HMGB1 or downstream signaling pathways such as Toll-like receptor 4 (TLR4) also abrogate neutrophil mobilization (1).

Importantly, the oncology field does not need to develop neutrophil-targeting agents, as it can benefit from compounds that have already been developed for treating inflammatory diseases, such as the asthma inhibitor zileuton (4). In addition, an IL-17 inhibitor has recently been approved for the treatment of psoriasis. Clearly, more experimental work is needed to better understand which features of tumors and which types of inflammatory environmental stimuli can induce prometastatic neutrophils and during which step of the metastatic cascade therapeutic intervention will be most effective.

Although preclinical studies suggest that monotherapy with neutrophil-targeting compounds is sufficient to inhibit metastasis (14), their use in cancer patients could be more effective when combined with well-established anticancer strategies such as chemo- and radiotherapy or targeted inhibition of oncogenic signal transduction. Based on the frequently observed immunosuppressive phenotype of tumor-educated neutrophils (2, 10), there is great potential in combinations with new cancer immunotherapy approaches that are currently revolutionizing the treatment of patients with various types of advanced cancer. This concept is supported by emerging evidence from clinical studies showing that high numbers of neutrophils relative to lymphocytes in the blood of melanoma patients are associated with poor response to immune checkpoint inhibition (11, 12), and from experimental studies in mice showing that neutrophils impair successful cancer immunotherapy (13, 14). New insights into the diverse mechanisms by which neutrophils promote metastasis will undoubtedly broaden the scientific basis for deploying neutrophil-targeting agents as part of multimodal treatment approaches for patients with advanced cancer in the near future.

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