The traditional model of hematopoiesis is based on unidirectional maturation of hematopoietic precursors into lineage-committed cells. However, recent studies indicate that mature B lymphocytes may demonstrate significant lineage plasticity. We and others have reported transdifferentiation of follicular lymphomas (FLs) into clonally related histiocytic/dendritic cell neoplasms. Here, we describe 2 patients with FL who developed clonally related Langerhans cell neoplasms. The first was a 52-year-old man diagnosed with FL, grade 1. He received immunochemotherapy and had stable disease for 8 years. He then developed increasing lymphadenopathy, and lymph node biopsy showed Langerhans cell sarcoma with no evidence of FL. The second patient was a 77-year-old woman who presented with lymphadenopathy, an abdominal mass, and pulmonary nodules. Lymph node biopsy showed both Langerhans cell histiocytosis and minimal involvement by FL, grade 1. In each case, a combination of immunoglobulin gene rearrangement and fluorescence in situ hybridization studies provided evidence to support a clonal relationship between the FL and Langerhans cell neoplasm. These cases provide striking examples of neoplastic transdifferentiation and expand the spectrum of lesions clonally identical to otherwise typical FL. Awareness of this phenomenon may aid in diagnosis when histologically dissimilar tumors arise synchronously or metachronously in patients with lymphoma.

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-α3β1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of β-catenin and Axin-2 as well as resistance to the inhibition in β-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-α3β1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.