Modulation of neutrophil granulocytes in the tumor microenvironment: Mechanisms and consequences for tumor progression

Abstract

Accumulating evidence indicates a critical role of myeloid cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages (TAMs), the significance of granulocytes in cancer has only recently begun to emerge. Increased numbers of neutrophil granulocytes have been observed both in the peripheral blood and in the tumor tissues of patients with different types of cancer. Importantly, these studies linked neutrophils to poor clinical outcome in cancer patients which suggests that these cells might have important tumor-promoting activities. Indeed, a number of functional in vitro and in vivo studies demonstrated that tumors stimulated neutrophils to promote angiogenesis and immunosuppression, as well as migration, invasion and metastasis of the tumor cells. Therefore, it became necessary to understand the mechanisms modulating the changes in the biology and functions of neutrophils in the context of the tumor microenvironment.

In this review we will discuss several functions of neutrophils that might contribute to tumor progression. Furthermore, we will address in detail the cellular and molecular mechanisms that control modulation of neutrophils in the tumor microenvironment, such as recruitment to the tumor site (chemotaxis), prolonged survival and enhanced release of protumoral mediators.

Introduction

Clinical and experimental evidence strongly indicates that inflammation is critical for carcinogenesis and cancer progression. In recent years increased attention has been given to the role of neutrophil granulocytes in cancer-associated inflammation. This interest stemmed from the rapidly accumulating number of studies that found an association between high neutrophil numbers and poor clinical outcome of cancer patients.

More than two decades ago, Shoenfeld and co-workers observed that in patients with several non-hematological malignancies, high blood leukocytosis significantly associated with shorter survival and presence of metastasis. Further analysis of the white blood cell subtypes indicated that an increase in the mature polymorphonuclear cells was mainly responsible for the leukocytosis observed in these patients [1]. Since then, many studies suggested that high neutrophil counts (mainly indicated by high neutrophil to lymphocyte ratios (NLR)) associated with poor clinical outcome in different types of cancer, such as colorectal [2], hepatocellular [3], renal [4], gastric [5], ovarian [6] or nasopharyngeal [7] cancer. In contrast to peripheral blood neutrophils, the clinical relevance of tumor-infiltrating neutrophils has only recently begun to emerge. Direct associations between tumor-infiltrating neutrophils and poor clinical outcome of patients have been described for several types of cancer including renal cancer [8], hepatocellular carcinoma [9], [10], non-small-cell lung carcinoma (NSCLC) [11], melanoma [12], head and neck squamous cell carcinoma (HNSCC) [13] or glioma [14] and, very recently, in gastric adenocarcinoma [15] and colorectal cancer [16]. Notably, most of the studies reporting these findings have been published in the last 3 years, which emphasizes the increasing importance and relevance of neutrophils in cancer biology. A detailed description and discussion of the clinical studies demonstrating the prognostic relevance of neutrophils in cancer patients is provided by another review in this series.