REVIEW
Cancer-Associated Myeloproliferation: Old Association, New Therapeutic Target

https://doi.org/10.4065/mcp.2010.0077Get rights and content

The association between malignancy and development of a paraneoplastic leukocytosis, the so-called leukemoid reaction, has long been appreciated. Although a leukemoid reaction has conventionally been defined as a peripheral blood leukocytosis composed of both mature and immature granulocytes that exceeds 50,000/μL, a less profound leukocytosis may be appreciated in many patients harboring a malignant disease. More recent insights have shed new light on this long-recognized association, because research performed in both murine models and cancer patients has uncovered multiple mechanisms by which tumors both drive myelopoiesis, sometimes leading to a clinically apparent leukocytosis, and inhibit the differentiation of myeloid cells, resulting in a qualitative change in myelopoiesis. This qualitative change leads to the accumulation of immature myeloid cells, which due to their immune suppressive effects have been collectively called myeloid-derived suppressor cells. More recently, myeloid cells have been shown to promote tumor angiogenesis. Cancer-associated myeloproliferation is not merely a paraneoplastic phenomenon of questionable importance but leads to the suppression of host immunity and promotion of tumor angiogenesis, both of which play an integral part in tumorigenesis and metastasis. Therefore, cancer-associated myeloproliferation represents a novel therapeutic target in cancer that, decades after its recognition, is only now being translated into clinical practice.

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MYELOID-DERIVED SUPPRESSOR CELLS

Myeloid-derived suppressor cells are a heterogeneous population of immature myeloid cells that are functionally defined by their ability to suppress host anti-tumor immunity.28, 29 The expansion of these cells is mediated by tumor- and stromal-derived factors that drive myelopoiesis and inhibit myeloid differentiation, including hematopoietic (eg, colony-stimulating factors [CSF]) and inflammatory (eg, interleukin [IL] 1, IL-6) cytokines, arachidonic acid metabolites, damage-associated

MYELOID CELLS AND TUMOR ANGIOGENESIS

Tumor- and stromal-derived proangiogenic factors promote formation of the tumor vasculature that is required for tumor growth and progression.80 Vascular endothelial growth factor A (VEGF-A) is a well-characterized factor that promotes tumor angiogenesis.81 Vascular endothelial growth factor A neutralization mediated by the monoclonal antibody bevacizumab inhibits tumor growth and angiogenesis in tumor xenografts and is now widely used in various human malignancies.80, 81 Tumor-infiltrating

THERAPEUTIC TARGETING OF CANCER-ASSOCIATED MYELOPOIESIS: TURNING TUMOR IMMUNITY “ON” AND ANGIOGENESIS “OFF”

Because tumor-associated myeloid cells, including MDSCs, suppress host anti-tumor immunity and promote tumor angiogenesis, targeting these cells represents a novel therapeutic approach in human cancers. The list of tumor-associated factors that drive myelopoiesis in the tumor-bearing host and promote activation, recruitment, and effector function of these myeloid cells continues to expand and presents many opportunities for therapeutic targeting of these cells. In contrast, the outright

CONCLUSION

Chronic inflammation has been implicated in the development of neoplastic disease for almost 150 years.141 Since then, many epidemiological and animal studies support this association.142 In the modern era, the association between malignant diseases, particularly when metastatic or locally advanced, and development of a leukocytosis has been appreciated, even though the importance of this association remained obscure. However, a growing body of work demonstrates that carcinogenesis and tumor

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