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Winning Abstracts from the 2011 Medical Student Abstract Competition: Neutrophil-Attracting Chemokines May Contribute to the Formation of a Pre-Metastatic Niche

Author: David E. Milbourn, The Brody School of Medicine at East Carolina University, Class of 2013

Introduction: The majority of cancer mortalities are a direct result of metastases or their complications. It is thus important to understand the factors that regulate the development and growth of malignant cells at metastatic sites. The term “pre-metastatic niche” has been used to define a particular microenvironment suitable for tumor cell attachment and growth to which primary tumor cells metastasize. It has been reported that bone marrow-derived hematopoietic progenitor cells (HPC) migrate to secondary locations prior to tumor cells. We hypothesize that neutrophils, which share many HPC markers, are one of the cell types that establish a pre-metastatic niche.

Methods: We tested our hypothesis in a murine Lewis Lung adenocarcinoma (LLCa) model. C57Bl/6 mice (n=23) were injected subcutaneously with 105 syngeneic LLCa and sacrificed 12-23 days later, before and after established lung metastases. Right lungs were homogenized and assayed for the neutrophil-attracting chemokines KC (CXCL1) and MIP-2 (CXCL2) by ELISA. Frozen sections (10 µm) of left lungs were stained with p-phenylenediamine and hydrogen peroxide to detect neutrophil myeloperoxidase (MPO) activity and with H&E to detect tumor cells.

Results: Most mice (16/23) had no visible or H&E-detectable lung metastases. Levels of both chemokines were low in normal lungs from naďve mice and in early pre-metastatic lung tissue. However, chemokine levels were significantly elevated after day 20 in pre-metastatic tissue (182±31.6 pg KC and 15.5±2.1 pg MIP-2 /mg protein) compared to normal lung (43.2±9.9 pg KC and 7.8±2.1 pg MIP-2/mg protein). Higher levels of KC, compared to MIP-2 were detected in all lung samples, which is characteristic of activated endothelium. The KC: MIP-2 ratio ranged from 6.0 ± 0.45 (in normal lung) to 30.5±8.8 in early pre-metastatic lung tissue. Neutrophil counts per microscopic field were similar in all tissues. However, neutrophil distribution was altered in tissue with detectable metastases; neutrophils percolated between blood vessels, migrated collectively and congregated around metastatic foci.

Conclusion: Neutrophil-attracting chemokines were elevated in lung tissue prior to tumor cell detection, supporting the hypothesis that neutrophils shape the microenvironment in pre-metastatic sites. The absolute number of lung-infiltrating neutrophils did not differ significantly over time. Studies are underway to determine if the neutrophil subtype varies with the development of metastases and if there is an increase in the N2 neutrophil subpopulation with a pro-tumor phenotype.

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