Keeping good and bad company: stromal cells in lymphoma

Tumors with an excessive amount of stroma have been recognized by pathologists for many decades, for example scirrhous carcinomas of the stomach or breast, fi brolamellar hepatocellular carcinoma, Hodgkin lymphoma (HL) or T-cell/histiocyte-rich large B-cell lymphoma, to name a few. Th e stroma in these tumors is part of their defi nition. Notwithstanding, virtually all tumors contain stromal cells, albeit to varying degrees [1]. Of interest, the nature of the stromal component has also been shown to correlate with prognosis or therapy outcome [1]. In vitro testing has further indicated that stromal cells are active determinants of tumor cell proliferation, diff erentiation and apoptosis [2]. Th erefore, the tumor stroma deservedly has become a major focus of study. Understanding tumor stroma may allow us to devise therapy to counteract its growth-stimulating or stimulate its growthinhibiting characteristics. Recently, novel insights have been gained into the potential role of the stroma in major lymphoma types, especially follicular lymphoma (FL), HL and diff use large B-cell lymphoma (DLBCL). Th e components of the immunological response in FL are clearly associated with survival. Using gene expression analysis, Dave et al . could discern diff erent types of immune response signatures, named immune-response 1 and immune-response 2, respectively [3]. Th e immuneresponse 1 gene signature was shown to be derived from infi ltrating T-cells and to a lesser degree from monocytes, whereas immune-response 2 genes were mainly derived from monocytic cells. Of interest, immune-response 1 genes were correlated with improved survival, whereas immuneresponse 2 genes were correlated with unfavorable survival [3]. However, subsequent studies using tissue microarrays and immunohistochemical methods for characterization of the stromal components have yielded confl icting results with regard to the prognostic impact of infi ltrating cells [4]. Th e latter may partly be due to diff erences in treatment of the patients in the studies [5]. Multiple studies have also indicated that the stromal response in HL is associated with survival diff erences [6]. More specifi cally, gene expression studies indicated that an increased number of infi ltrating macrophages is associated with a less favorable outcome, as demonstrated for FL [7]. Other studies using immunohistochemistry on tissue sections have yielded similar fi ndings [6]. Equally, a stromal gene expression signature can invariably be detected in DLBCL [8 – 10]. DLBCL is molecularly heterogeneous, and can in more than 50% of cases be cured with an anthracycline-based chemotherapy combined with rituximab immunotherapy. Th e addition of immunotherapy improved the survival of patients compared with chemotherapy alone [11]. Th is is true for the two major molecular subtypes of the disease, germinal center B-cell-like and activated B-cell-like [10,12]. However, there still remains an important proportion of patients who cannot be cured with this therapy. Of interest, the stromal component in DLBCL as well as the expression of surface molecules that are important for interaction with stromal cells such as human leukocyte antigen class I and II molecules have proved to be important determinants of survival, irrespective of the molecular subtype [8]. Lenz et al . have shown by gene expression analysis of DLBCL, including expression analysis of fl ow-sorted samples, that especially two types of stromal response determine outcome, called stromal-1 and stromal-2, which result in an improved or worse survival, respectively, for patients treated with immunochemotherapy [10]. Th e stromal-1 response involves connective tissue growth factor and components of the extracellular matrix such as fi bronectin, osteonectin, collagen and laminin isoforms, as well as enzymatic modifi ers of collagen and extracellular matrix components. Th e stromal-2 response consists of genes that encode key regulators of angiogenesis, such as, for example, vascular endothelial growth factor, as well as endothelial cell markers such as CD31, and adipocyte markers. Of interest, the stromal-1 response is mediated by infi ltrating monocyte-derived cells. Th e favorable prognostic impact of monocyte-derived cells suggest another role of these cells in DLBCL compared with FL and HL. In this issue of Leukemia and Lymphoma , Rydstr o m et al . show that expression of CD40 by diff use large B-cell lymphoma, a putative marker for favorable prognosis in DLBCL, is associated with the up-regulation of genes coding for extracellular matrix components as well as proteolytic enzymes, thus approaching the stromal-1 signature [13]. Whether activation through CD40 expressed by diff use large L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re . c om b y 61 . 2 21 . 3 3. 39 o n 05 /2 0/ 14