We have read with great interest the comprehensive review by Skinnider and Mak that summarizes the current literature regarding the expression and activity of cytokines in classical Hodgkin disease (cHD), a unique pathologic condition in which a minority of clonal neoplastic cells are embedded in a heterogeneous background of nonmalignant cells.1 As stated by the authors, given the peculiar features of HD, bona fide HD-derived cell lines remain to date invaluable tools for investigating the cytokine-dependent interactions of Hodgkin–Reed Sternberg (H-RS) cells. Nevertheless, information from these studies should be always confirmed and validated by other studies carried out in the context of fresh HD-involved tissues or involving primary H-RS cells. By using such an approach, we have described 2 cytokine circuitries allegedly operating in HD that involve interleukin-3 (IL-3), stem cell factor (SCF), and their corresponding receptors (Rs).2-5
As opposed to data reported by Skinnider and Mak,1 our evidence seems to suggest a role for IL-3 in H-RS cell proliferation and survival.2 In this regard, we demonstrated that IL-3 can promote the clonogenic growth of HD-derived cells and is able to partially rescue them from apoptosis induced by serum deprivation.2 Accordingly, HD-derived cell lines express mRNA and protein of the IL-3Rαβ complex, whereas primary H-RS cells from all cHD cases tested can be stained by anti–IL-3Rα antibodies.2
On the other hand, data reported by Skinnider and Mak indicating the lack of IL-3 production by HD-derived cell lines1 are consistent with our findings obtained by using a technical approach as sensitive as reverse transcriptase–polymerase chain reaction.2
Moreover, the notion that IL-3 mRNA was detected by Northern analysis in some cases of cHD-involved tissues, as reported by Skinnider and Mak,1 is in keeping with data from our group demonstrating the ability of HD-derived cells to modulate the production of IL-3 by T cells.3 In fact, preactivated purified T cells, when cultured along with paraformaldehyde-fixed HD-derived cells, release significantly higher amounts of IL-3 than in cultures carried out without fixed HD-derived cells.3
The expression of SCF receptor (SCFR)/c-kit by the neoplastic component of cHD has been described by us some years ago.4 This data, given the notion that fibrosis is a common feature of cHD-involved tissues6 and SCF is produced by several stomal cells including fibroblasts,7strongly suggested a role of SCF/SCFR pair in cHD. The formal proof of this has been recently provided.5 By using HD-derived cell lines and fibroblasts from HD-involved lymph nodes (HDF), we demonstrated the expression of c-kit in HD-derived cells and of SCF in primary HDF.5 Moreover, functional experiments have shown the in vitro adhesion of HD-derived cells to HDF through c-kit/SCF interactions, as well as the capability of SCF to increase the growth/survival of HD-derived cells, and to partially rescue HD-derived cells from apoptosis induced by serum starvation.5
To improve the knowledge of the various cytokine pathways sustaining H-RS cell proliferation and survival may eventually contribute to the design of innovative therapies for relapsed/refractory HD patients.
