Neutrophils support lung colonization of metastasis-initiating breast cancer cells

By S. Wculek, I. Malanchi. Nature, 2015

935 citations recorded by the source corpus.

Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression.

Subfields: Immunology, Oncology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/f81f20297e622153fad5113a8e8e6c6781fe5b4b

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Citations in the corpus

Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “Neutrophils have been proposed to be pioneer cells in the lung premetastatic niche, supporting the arrival of disseminated cells in the MMTV-PyMT model (Wculek and Malanchi 2015).”
The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “Moreover, neutrophil-derived leukotrienes selectively expand tumor cells (107).”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “This niche formation may involve the actions of VEGFR+ bone marrow progenitors (Kaplan et al., 2005), myeloid-derived suppressor cells (MDSCs) (Psaila and Lyden, 2009), or neutrophils (Wculek and Malanchi, 2015).”
Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, positive): “These results suggest that T cell infiltration reduces the initiation and/or growth of metastatic lesions, consistent with results from other systems (Wculek and Malanchi, 2015).”
Characteristics and Significance of the Pre-metastatic Niche. (2016, background): “Neutrophil-secreted leukotrienes may support lung colonization and metastasis of breast cancer cells (Wculek and Malanchi, 2015).”
The microenvironmental landscape of brain tumors (2017, background): “…has been shown in other metastatic organs that are not subject to immune privilege (Casbon et al., 2015; Coffelt et al., 2015; Liu et al., 2016; Wculek and Malanchi, 2015), supporting the concept that, in the context of a tumor, the brain may be aberrantly exposed to pathologic inflammation…”
CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma (2016, positive): “Indeed, neutrophils have recently been shown to support metastatic colonization by breast cancer cells (Wculek and Malanchi, 2015).”