Ofer Fainaru, Shay Hantisteanu, Gili Paz, Niv Pencovich, Mordechai Hallak

Laboratory of Reproductive Immunology, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center

Angiogenesis is a rate-limiting step in various developmental processes as well as tumor progression and metastasis. Immature myeloid cells (IMCs) play important roles in both physiological and pathological vascularization. We have previously shown that although largely pro-angiogenic, the global transcriptional pattern of IMCs is significantly influenced by the surrounding microenvironment. Differential gene expression can be detected within dormant versus aggressive tumors, as well as in normal angiogenic tissue such as placenta.

In this study we further evaluated the differences between IMCs derived from the mouse placenta, representing normal angiogenesis, and those derived form malignant tumors. We show that in tumors the Ly6G^med/Ly6C^high “monocytic” subpopulation of IMCs is enriched compared to Ly6G^high/Ly6C^med “granulocytic” subpopulation within the placenta. This shift corresponds to profound changes in global gene expression between tumor- and placenta derived IMCs. Tumor derived IMCs express genes that are involved in tumor angiogenesis and progression, as well as cell cycle and proliferation. On the other hand, placental IMCs express genes that play role in hematopoiesis and angiogenesis of the reproductive system. Additionally, increased proportion of genes that were highly expressed in placenta IMCs were also highly expressed in dormant compared to aggressive tumors.  Finally, we observed differences in the ability of IMCs isolated from either tumor or placenta to promote angiogenesis in matrigel plugs implanted in mice.

The data suggest that IMCs respond and function differently in malignant versus normal environments. Deciphering the properties of normal vs. pathologic angiogenesis holds promise in the design of new modalities for cancer therapy.