Transforming growth factor superfamily ligands and links to tumorigenesis

Activin A, a member of the transforming growth factor-b (TGF-b) superfamily formed by homodimerization of Inhibin-b A (INHBA), plays a major role in cell differentiation, proliferation, apoptosis, and inflammation through activation of mitogen-activated protein kinase (MAPK) and SMAD signaling pathways [1]. The prognostic impact of INHBA expression has been studied in a wide array of solid tumors. In gastric cancer, high expression of INHBA, as compared to normal tissue, correlates with poorer outcomes and has been identified as an independent prognostic factor after surgery with curative intent [2,3]. In urothelial cancer, Lee et al. identified an association between an overexpression of INHBA and adverse outcomes [4]. However, opposing effects and contradictory outcomes have been also observed. For example, Togashi et al. showed that Activin A exhibits tumor suppressor activity in pancreatic cancer cells [5]. However, a later study by the same team reported that pancreatic cancer patients with higher Activin A levels had a shorter survival period, as compared to those with lower levels (p1⁄4 .034) [6]. In addition, a xenograft mouse-model of INHBA-overexpressed cells resulted in larger tumor volume and early death in these mice [6]. Overall, it appears that INHBA can promote tumor progression in a subset of pancreatic cancer patients, a finding that complicates the results of Togashi’s earlier study [6]. Very little is known regarding the role of INHBA in hematologic malignancies. Huang et al. showed that that K562 erythroleukemia cells treated with Activin A are sensitized to subtoxic imatinib concentrations leading to enhanced growth inhibition and apoptosis [7]. Further, Huang et al. reported a decrease in BCR-ABL protein levels after treatment of K562 cells with Activin A and imatinib [7]. In multiple myeloma, Vallet et al. previously reported that Activin A is highly expressed in patients with more than one osteolytic lesion compared to patients with one osteolytic lesion or less [8]. A related study showed that an activinblocking antibody diminished the effect of IL-3 on osteoclastogenesis in vivo and in vitro [9], while a more recent study demonstrated that Activin A suppresses myeloma mouse NS-1 cell viability and induces cell apoptosis [10]. Notably, another recent study in patients with acute myeloid leukemia (AML) provided evidence for an association of high INHBA levels with older age (>60), mutant FLT3 expression, and a lower remission rate [11]. These few studies highlight that INHBA plays different roles in different diseases and suggests that other factors could be contributing to the results that are seen. In issue 59(5) of Leukemia and Lymphoma, Jiang et al. are the first to report on the role of INHBA in DLBCL [12]. The authors found low levels of INHBA in tonsils with primary DLBCL (GCB or non-GCB subtype), compared to those in benign tonsils. Furthermore, patients with low INHBA mRNA levels had reduced overall and progression-free survival, as compared to those with high levels of INHBA mRNA levels [12]. Importantly, ectopic expression of INHBA in DLBCL cell lines led to a decrease in cell proliferation, increased spontaneous apoptosis, and cell cycle arrest in in vitro studies and suppressed xenograft (mouse) tumor growth in vivo [12]. In addition, INHBA sensitized DLBCL cells to chemotherapy [12]. The authors concluded that INHBA functions as a tumor suppressor is a potential prognostic indicator and may have a role for novel therapy in DLBCL [12]. Diffuse large B-cell lymphoma is a heterogeneous disease. Some patients can be cured, but about onethird of patients do not achieve durable remissions and develop relapsed/refractory disease. In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin (COO) and the