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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
Results: Most mice (16/23) had no visible or
H&E-detectable lung metastases. Levels of both chemokines were
low in normal lungs from naïve 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
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
December Issue of IMpact