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, fibrolamellar hepatocellular carcinoma, Hodgkin lymphoma (HL) or T-cell/histiocyte-rich large B-cell lymphoma, to name a few. The stroma in these tumors is part of their definition. 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, differentiation and apoptosis [2]. Therefore, 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 growth-inhibiting characteristics.

Recently, novel insights have been gained into the potential role of the stroma in major lymphoma types, especially follicular lymphoma (FL), HL and diffuse large B-cell lymphoma (DLBCL). The components of the immunological response in FL are clearly associated with survival. Using gene expression analysis, Dave et al. could discern different types of immune response signatures, named immune-response 1 and immune-response 2, respectively [3]. The immune-response 1 gene signature was shown to be derived from infiltrating 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 immune-response 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 conflicting results with regard to the prognostic impact of infiltrating cells [4]. The latter may partly be due to differences in treatment of the patients in the studies [5].

Multiple studies have also indicated that the stromal response in HL is associated with survival differences [6]. More specifically, gene expression studies indicated that an increased number of infiltrating macrophages is associated with a less favorable outcome, as demonstrated for FL [7]. Other studies using immunohistochemistry on tissue sections have yielded similar findings [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. The addition of immunotherapy improved the survival of patients compared with chemotherapy alone [11]. This 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 flow-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]. The stromal-1 response involves connective tissue growth factor and components of the extracellular matrix such as fibronectin, osteonectin, collagen and laminin isoforms, as well as enzymatic modifiers of collagen and extracellular matrix components. The 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 infiltrating monocyte-derived cells. The 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, Rydström et al. show that expression of CD40 by diffuse 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 diffuse large B-cell lymphoma provokes a beneficial pro-inflammatory response is therefore an interesting thought. This hypothesis is especially of interest because of possible therapeutic intervention with anti-CD40 stimulating antibodies. However, whether stimulation through CD40 expressed by lymphoma cells provokes a stromal-1 response needs yet to be proved.

In conclusion, stromal cells are clearly associated with lymphoma survival. Stromal signatures, especially data generated from gene expression analysis, can therefore be used as a prognosticator for survival. However, immunophenotypic markers for stromal cell subsets using immunohistochemistry on paraffin sections can likely not detect the several functional subsets of stromal cells [14], and may explain some of the conflicting results with regard to predicting prognosis in lymphoma using these techniques [4,6,15–17]. In addition, the stromal response gene signatures, while useful as a disease prognosticator, are not necessarily active determinants of lymphoma biology. Monocytes have for example been shown to support diffuse large B-cell lymphoma growth in vitro, apparently contradicting the association of favorable prognosis associated with a stromal-1 response [18]. More robust data from in vitro models for the various lymphoma types are needed to unravel the functional role of stromal cells on lymphoma biology. Only the latter will perhaps allow us to devise rational treatments targeting the stromal response to improve lymphoma survival.

Potential conflict of interest

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