Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF.

LIM-homeodomain (LIM-HD) transcription factors form a combinatorial 'LIM code' that contributes to the specification of cell types. In the ventral spinal cord, the binary LIM homeobox protein 3 (Lhx3)/LIM domain-binding protein 1 (Ldb1) complex specifies the formation of V2 interneurons. The additional expression of islet-1 (Isl1) in adjacent cells instead specifies the formation of motor neurons through assembly of a ternary complex in which Isl1 contacts both Lhx3 and Ldb1, displacing Lhx3 as the binding partner of Ldb1. However, little is known about how this molecular switch occurs. Here, we have identified the 30-residue Lhx3-binding domain on Isl1 (Isl1 LBD ). Although the LIM interaction domain of Ldb1 (Ldb1 LID ) and Isl1 LBD share low levels of sequence homology, X-ray and NMR structures reveal that they bind Lhx3 in an identical manner, that is, Isl1 LBD mimics Ldb1 LID . These data provide a structural basis for the formation of cell type-specific protein-protein interactions in which unstructured linear motifs with diverse sequences compete to bind protein partners. The resulting alternate protein complexes can target different genes to regulate key biological events.

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IntroductionGastric mucosa-associated lymphoid tissue (MALT) B-cell lymphoma develops in the context of long-term infection with the Gram-negative gastric bacterium Helicobacter pylori. 1-3 Persistent infection with H pylori causes chronic gastritis that, in some people, can develop into more organized gastric mucosa-associated lymphoid tissue (MALT) with histologic similarity to the Peyer patches of the small intestine. 4 The disease progresses when individual malignant clones grow out, displace the benign lymphoid tissue, and ultimately form the lymphoepithelial lesions that are a hallmark of MALT lymphoma. 5,6 In its early stages, gastric MALT lymphoma is believed to be an antigen-dependent disease; H pylori infection is detectable in a large majority of cases. 1,3,7 Eradication therapy induces tumor regression in approximately 75% of patients at this stage. 8,9 Early-stage low-grade MALT lymphoma is generally considered an indolent tumor due to its slow growth, low proliferation rates, and minimal propensity for spreading. At later stages, however, the tumors can eventually undergo high-grade transformation or acquire one of several known characteristic chromosomal translocations, thereby rendering the lymphoma independent of antigen exposure and refractory to H pylori eradication therapy.In contrast to cases with chromosomal rearrangements, which grow autonomously due to constitutive activation of the nuclear factor B (NF-B) signaling pathway brought about by overexpression of MALT-1, B-cell leukemia 10 (Bcl-10), or production of the Baculovirus IAP repeat-containing 3 (API2)-MALT1 fusion protein (reviewed in Isaacson and Du), 5 little is known about the pathogenesis of early MALT lymphoma. Several studies have implicated the abundant population of tumor-infiltrating T cells in providing growth signals to tumor B cells. [10][11][12] In one study, depletion of T cells was shown to abrogate the proliferation of explanted MALT lymphoma cultures. 12 We and others have reported that MALT lymphomas express high levels of interleukin-4 (IL-4) and other T helper 2 cytokines in vivo, supporting a role for T helper 2-polarized T-helper responses in early MALT lymphomagenesis. 10,11 An alternative possibility is that early stage MALT lymphoma B cells receive signals via antigenic stimulation through their B-cell receptor (BCR), which would lead to NF-B activation, survival, and proliferation. Indeed, MALT lymphoma cells carry functional, rearranged, and somatically mutated immunoglobulin genes on their surface. 13,14 Sequence analysis of the V H genes suggests that the tumor cells have undergone positive selection in germinal centers. [14][15][16] Intraclonal variation caused by ongoing somatic mutation and/or replacement of a part of the variable heavy segment (receptor revision) has been reported. [15][16][17] Despite these clear results, the search for a target antigen has proven difficult and has yielded controversial results, either providing evidence for reactivity toward certain structures of normal human tissu...

The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect. Significance: Although initial tumor responses to kinase inhibitors can be significant, therapeutic benefit is often limited by the emergence of resistance (e.g., as a consequence of mutations in the drug target or through activation of alternative pathways to bypass dependence on the original target). Because the activation of alternative growth-promoting kinases by stimulation with their cognate ligands can constitute such a bypass mechanism, the identification of growth factors as possible mediators of resistance to kinase inhibitors is of clinical interest. Cancer Discov; 2(10); 948–59. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 857.

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of chronic inflammation caused by Helicobacter pylori infection. Most pathophysiological features of the early stages of MALT lymphomagenesis can be reproduced by experimental infection of BALB/c mice with Helicobacter species. We have previously shown that MALT lymphomas are infiltrated by T-helper cell type 2-polarized T cells and that human and murine tumor B cells carry polyreactive surface immunoglobulins. Using the murine model of the disease, in this study we show that explanted tumor B cells proliferate upon stimulation with the same panel of self and foreign antigens that are recognized by their surface antibodies. Tumor cell proliferation is strongly enhanced by the presence of intratumoral CD4(+) T cells in a CD40/CD40L-independent manner. A large proportion of tumor-infiltrating CD4(+) T cells are CD25(+)FoxP3(+) regulatory T cells (Tregs) with highly suppressive activity, which are recruited by the tumor cells through secretion of the Treg-attracting chemokines CCL17 and CCL22. The depletion of CD25(+) cells was as efficient as CD4(+) T cell depletion in blocking tumor growth in vitro and in vivo. In conclusion, our data suggest that B-cell receptor-derived signals cooperate with T-helper cell signals in driving the progression of MALT lymphoma, providing an explanation for the unique antigen dependence of this B-cell malignancy.

Chromosomal rearrangements of the mixed lineage leukemia (MLL/KMT2A) gene leading to oncogenic MLL-fusion proteins occur in ~10% of acute leukemias and are associated with poor clinical outcomes, emphasizing the need for new treatment modalities. Inhibition of the DOT1-like histone H3K79 methyltransferase (DOT1L) is a specific therapeutic approach for such leukemias that is currently being tested in clinical trials. However, in most MLL-rearranged leukemia models responses to DOT1L inhibitors are limited. Here, we performed deep-coverage short hairpin RNA sensitizer screens in DOT1L inhibitor-treated MLL-rearranged leukemia cell lines and discovered that targeting additional nodes of MLL complexes concomitantly with DOT1L inhibition bears great potential for superior therapeutic results. Most notably, combination of a DOT1L inhibitor with an inhibitor of the MLL-Menin interaction markedly enhanced induction of differentiation and cell killing in various MLL disease models including primary leukemia cells, while sparing normal hematopoiesis and leukemias without MLL rearrangements. Gene expression analysis on human and murine leukemic cells revealed that target genes of MLL-fusion proteins and MYC were suppressed more profoundly upon combination treatment. Our findings provide a strong rationale for a novel targeted combination therapy that is expected to improve therapeutic outcomes in patients with MLL-rearranged leukemia.

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) develops in the chronically inflamed mucosa of patients infected with the bacterial pathogen Helicobacter pylori. Here we use patient material, primary gastric lymphoma cell cultures, and a preclinical model of the disease to examine the role of microRNA (miRNA)-mediated posttranscriptional regulation-focusing in particular on miR-203 and its target ABL1-in gastric MALT lymphomagenesis. Microarray-based miRNA expression profiling revealed a strong downregulation of the putative tumor suppressor miRNA miR-203 in human MALT lymphoma samples, which resulted from extensive promoter hypermethylation of the miR-203 locus and coincided with the dysregulation of the miR-203 target ABL1 in lymphoma biopsies compared with matched adjacent normal material from the same patients. Treatment of lymphoma B cells with demethylating agents led to increased miR-203 expression and the concomitant downregulation of ABL1, confirming the epigenetic regulation of this miRNA. Ectopic reexpression of miR-203 by transfection of a human lymphoma cell line or lentiviral transduction of explanted primary MALT lymphoma cells was sufficient to prevent tumor cell proliferation in vitro. Similarly, the treatment of primary MALT lymphoma cells with the ABL inhibitors imatinib and dasatinib prevented tumor cell growth. Finally, we show that the treatment of tumor-bearing mice with imatinib induces MALT lymphoma regression in a preclinical model of the disease, implicating ABL1 in MALT lymphoma progression. In summary, our results show that the transformation from gastritis to MALT lymphoma is epigenetically regulated by miR-203 promoter methylation and identify ABL1 as a novel target for the treatment of this malignancy. Cancer Res; 71(10); 3616-24. Ó2011 AACR.