Tissue Inhibitor of Metalloproteinases-1 Promotes Liver Metastasis by Induction of Hepatocyte Growth Factor Signaling

Kopitz, Charlotte; Gerg, Michael; Bandapalli, Obul Reddy; Ister, Dilek; Pennington, Caroline J.; Hauser, Stephanie; Flechsig, Christin; Krell, Hans Willi; Antolovic, Dalibor; Brew, Keith; Nagase, Hideaki; Stangl, Manfred; Weyhern, Claus W. Hann von; Brücher, Björn L.D.M.; Brand, Karsten; Coussens, Lisa M.; Edwards, Dylan R.; Krüger, Achim

doi:10.1158/0008-5472.can-07-0232

Cited by 130 publications

(148 citation statements)

References 44 publications

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“…Our study demonstrates that anti-inflammatory cytokines HGF and IL-11, as well as gp130, the signalling receptor chain common to IL-11 and IL-6, are upregulated in PV independently of JAK2V617F. In addition, TIMP-1, a molecule that controls HGF activity and has been reported to be over-expressed in primary myelofibrosis, was also found to be elevated in PV (Ho et al, 2007;Kopitz et al, 2007). HGF, IL-11 and IL-6 are produced by JAK2WT BMMSCs and JAK2V617F-mutated erythroid progenitors; they act in cascade, activate the STAT3 pathway and stimulate myeloid hematopoiesis.…”

Section: Discussionmentioning

confidence: 49%

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

et al. 2010

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The V617F activating mutation of janus kinase 2 (JAK2), a kinase essential for cytokine signalling, characterizes Polycythemia vera (PV), one of the myeloproliferative neoplasms (MPN). However, not all MPNs carry mutations of JAK2, and in JAK2-mutated patients, expression of JAK2V617F does not always result in clone expansion. In the present study, we provide evidence that inflammation-linked cytokines are required for the growth of JAK2V617F-mutated erythroid progenitors. In a first series of experiments, we searched for cytokines overexpressed in PV using cytokine antibody (Ab) arrays, and enzyme-linked immunosorbent assays for analyses of serum and bone marrow (BM) plasma, and quantitative reverse transcription-PCRs for analyses of cells purified from PV patients and controls. We found that PV patients over-expressed anti-inflammatory hepatocyte growth factor (HGF) and interleukin-11 (IL-11), BM mesenchymal stromal cells (BMMSCs) and erythroblasts being the main producers. In a second series of experiments, autocrine/paracrine cytokine stimulation of erythroblasts was blocked using neutralizing Abs specific for IL-11 or c-MET, the HGF receptor. The growth of JAK2V617F-mutated HEL cells and PV erythroblasts was inhibited, indicating that JAK2-mutated cells depend on HGF and IL-11 for their growth. Additional experiments showed that transient expression of JAK2V617F in BaF-3/erythropoietin receptor cells, and invalidation of JAK2V617F in HEL cells using anti-JAK2 small interfering RNA, did not affect HGF and IL-11 expression. Thus, anti-inflammatory HGF and IL-11 are upregulated in PV and their overproduction is not a consequence of JAK2V617F. As both cytokines contribute to the proliferation of PV erythroblasts, blocking the c-MET/ HGF/IL-11 pathways could be of interest as an additional therapeutic option in PV.

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Section: Discussionmentioning

confidence: 49%

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

et al. 2010

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“…Interestingly, invasive NM23-H1-silenced cells expressed high levels of TIMP-1 (data not shown). Enhanced expression of this endogenous MMP inhibitor has been linked to poor prognosis in human cancer types and was shown to promote hepatocyte growth factor/scatter factor signaling and downstream expression of MMP-2 and MMP-9 in the liver (37).…”

Section: Discussionmentioning

confidence: 99%

Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

et al. 2010

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Loss of NM23-H1 expression correlates with the degree of metastasis and with unfavorable clinical prognosis in several types of human carcinoma. However, the mechanistic basis for the metastasis suppressor function of NM23-H1 is obscure. We silenced NM23-H1 expression in human hepatoma and colon carcinoma cells and methodologically investigated effects on cell-cell adhesion, migration, invasion, and signaling linked to cancer progression. NM23-H1 silencing disrupted cell-cell adhesion mediated by E-cadherin, resulting in β-catenin nuclear translocation and T-cell factor/lymphoid-enhancing factor-1 transactivation. Further, NM23-H1 silencing promoted cellular scattering, motility, and extracellular matrix invasion by promoting invadopodia formation and upregulating several matrix metalloproteinases (MMP), including membrane type 1 MMP. In contrast, silencing the related NM23-H2 gene was ineffective at promoting invasion. NM23-H1 silencing activated proinvasive signaling pathways involving Rac1, mitogen-activated protein kinases, phosphatidylinositol 3-kinase (PI3K)/Akt, and src kinase. Conversely, NM23-H1 was dispensable for cancer cell proliferation in vitro and liver regeneration in NM23-M1 null mice, instead inducing cellular resistance to chemotherapeutic drugs in vitro. Analysis of NM23-H1 expression in clinical specimens revealed high expression in premalignant lesions (liver cirrhosis and colon adenoma) and the central body of primary liver or colon tumors, but downregulation at the invasive front of tumors. Our findings reveal that NM23-H1 is critical for control of cell-cell adhesion and cell migration at early stages of the invasive program in epithelial cancers, orchestrating a barrier against conversion of in situ carcinoma into invasive malignancy. Cancer Res; 70(19); 7710-22. ©2010 AACR.

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“…HGF can then bind to c-Met expressed in many cancer cells and can increase their invasive and migratory capacity (Nakamura et al 1997). The MMP inhibitor TIMP-1 may also act as a key regulator of HGF/c-Met signaling through suppression of metalloproteinase-10 (ADAM-10) (Kopitz et al 2007). Other paracrine signals involving TGF-␤, EGF, and insulin growth factor (IGF), as well as Wnt1, likely mediate mutually supportive cross-talk between the stromal cells and tumor cells (Bhowmick et al 2004).…”

Section: Far-away Fibroblasts: Setting the Scenementioning

confidence: 99%

Migratory neighbors and distant invaders: tumor-associated niche cells

Wels

Kaplan²,

Rafii³

et al. 2008

Genes Dev.

355

301

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The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor-stromal and stromal-stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies.Understanding the complex biological networks at play in metastasis requires a precise detailing of the molecular and cellular pathways involved in local and systemic migration. The long prevailing model of invasion and metastasis has focused on the adhesive and migratory capabilities that are intrinsic to tumor cells (Hanahan and Weinberg 2000). Meanwhile, we are becoming increasingly aware that tumors are composed of genetically altered malignant cells along with a heterogeneous population of stromal cells, whose dynamic interactions can profoundly enhance tumor progression and metastasis. Through the production of chemokines, growth factors, and matrix-degrading enzymes (Table 1), supportive cells-including fibroblasts, immune cells, and bone marrow (BM)-derived stem and progenitor cells-support blood vessel formation, break down basement membrane barriers, and attract tumor cells to distant sites. Tumor cells are constantly giving instructions, not only by direct cell-cell interactions, but also by secreted factors that "activate" normal host cells at both proximal and distal sites to migrate, eventually developing permissive niches that, in return, promote tumor cell survival and proliferation. The focus of this review is on the cellular constituents of the primary and metastatic tumor microenvironments, with emphasis on their migratory pathways. We hope to convey that the tumor and host cell interaction is truly reciprocal; while host cells may support tumor cells, tumor cells in turn modulate the microenvironments within which they reside. Furthermore, we highlight that cancer is a systemic disease, encompassing collective cell movements of tumor and stromal cells that are a prerequisite for tumor cell invasion and metastasis. Intrinsic tumor cell migratory capabilitiesInherent to the metastatic process is the capability of tumor cells to migrate through connective tissue barriers comprising cell-cell adherent junctions, basement membranes, and interstitial tissue stroma. This intrinsic migratory behavior is highly dependent on the interplay between adhesive and proteolytic activities. Tumor cell down-regulation of proteins mediating cell-cell interactions, such as cadherins, leads to changes in cell signaling, actin-based cytoskeletal structure, and eventual dissociation from n...

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Tissue Inhibitor of Metalloproteinases-1 Promotes Liver Metastasis by Induction of Hepatocyte Growth Factor Signaling

Cited by 130 publications

References 44 publications

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Migratory neighbors and distant invaders: tumor-associated niche cells

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