Abstract
Myeloid cells promote the development of distant metastases, but little is known about the molecular mechanisms underlying this process. Here we have begun to uncover the effects of myeloid cells on cancer cells in a mouse model of liver metastasis. Monocytes/macrophages, but not granulocytes, isolated from experimental liver metastases stimulated migration and invasion of MC38 colon and Lewis lung carcinoma cells. In response to conditioned media from tumor-infiltrating monocytes/macrophages, cancer cells upregulated S100a8 and S100a9 messenger RNA expression through an extracellular signal-related kinase-dependent mechanism. Suppression of S100A8 and S100A9 in cancer cells using short hairpin RNA significantly diminished migration and invasion in culture. Downregulation of S100A8 and S100A9 had no effect on subcutaneous tumor growth. However, colony size was greatly reduced in liver metastases with decreased invasion into adjacent tissue. In tissue culture and in the liver colonies derived from cancer cells with knockdown of S100A8 and S100A9, MMP2 and MMP9 expression was decreased, consistent with the reduction in migration and invasion. Our findings demonstrate that monocytes/macrophages in the metastatic liver microenvironment induce S100A8 and S100A9 in cancer cells, and that these proteins are essential for tumor cell migration and invasion. S100A8 and S100A9, however, are not responsible for stimulation of proliferation. This study implicates S100A8 and S100A9 as important mediators of tumor cell aggressiveness, and highlights the therapeutic potential of S100A8 and S100A9 for interference of metastasis.
Highlights
IntroductionThese myeloid cells are highly heterogeneous with cells of both the monocytic and granulocytic lineages, and have considerable phenotypic plasticity with both positive and negative effects on tumor growth and metastasis.[1,2] The balance between anti-tumor and pro-tumor functions can be dependent on polarization state, interaction with the tumor microenvironment and/or the tumor type.[3,4,5] Understanding the actions of myeloid cells on cancer cells could be essential in distinguishing, and possibly manipulating, the positive from the negative effectors.[6,7]
To determine the mechanisms through which myeloid cells support the development of liver metastasis, we first investigated whether augmentation of some tumor cell properties by myeloid cells could be duplicated in tissue culture
We found that the tumor colonies generated by MC38 or Lewis lung carcinoma (LLC) cancer cells were infiltrated by CD11b+ myeloid cells that could be divided into three distinct groups based on their Gr1 expression (Gr1high, Gr1mid and Gr1low)
Summary
These myeloid cells are highly heterogeneous with cells of both the monocytic and granulocytic lineages, and have considerable phenotypic plasticity with both positive and negative effects on tumor growth and metastasis.[1,2] The balance between anti-tumor and pro-tumor functions can be dependent on polarization state, interaction with the tumor microenvironment and/or the tumor type.[3,4,5] Understanding the actions of myeloid cells on cancer cells could be essential in distinguishing, and possibly manipulating, the positive from the negative effectors.[6,7]. We previously examined the effects of infiltrating myeloid cells on experimental liver metastases generated by intrasplenic inoculation of MC38 colon and Lewis lung carcinoma (LLC) cells. These metastatic colonies were infiltrated by CD11b+ cells comprising granulocytes and monocytes/macrophages. To begin to understand how these effects were mediated, we isolated cancer cells after removal of the CD11b+ myeloid cells
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