Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Gerg, Michael; Kopitz, Charlotte; Schaten, Susanne; Tschukes, Alexander; Kahlert, Christoph; Stangl, Manfred; Weyhern, Claus W. Hann von; Brücher, Björn L.D.M.; Edwards, Dylan R.; Brand, Karsten; Krüger, Achim

doi:10.1158/1541-7786.mcr-07-2032

Cited by 24 publications

(36 citation statements)

References 56 publications

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“…Lentiviruses were generated using respective plasmids and the ViraPower TM lentiviral expression system (Invitrogen, Karlsruhe, Germany). Transduction was done as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

“…This phenomenon is of great relevance as the invasive steps of tumor progression are characterized by imbalances in the "protease web," comprising the complex network of proteases, their inhibitors, and effector molecules (20 -22). Specifically, up-regulation of MMP-9 in the tumor microenvironment (23,24) accounts for the degradation of the basal membrane and the remodeling of the extracellular matrix (ECM) to clear the path for tumor cells during the invasive steps of metastasis (25). Another important mediator of tumor cell scattering from already established metastases is the hepatocyte growth factor (HGF) signaling pathway (26), initiated by binding of HGF, originally also described as the "scatter factor" (27), to its receptor MET.…”

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confidence: 99%

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Identification of a Survival-independent Metastasis-enhancing Role of Hypoxia-inducible Factor-1α with a Hypoxia-tolerant Tumor Cell Line

Schelter

Gerg

Halbgewachs

et al. 2010

Journal of Biological Chemistry

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During tumor progression, malignant cells must repeatedly survive microenvironmental stress. Hypoxia-inducible factor-1 (HIF-1) signaling has emerged as one major pathway allowing cellular adaptation to stress. Recent findings led to the hypothesis that HIF-1␣ may enhance the metastatic potential of tumor cells by a survival-independent mechanism. So far it has not been shown that HIF-1␣ also directly regulates invasive processes during metastasis in addition to conferring a survival advantage to metastasizing tumor cells. In a hypoxia-tolerant tumor cell line (L-CI.5s), which did not rely on HIF-1 signaling for viability in vitro and in vivo, knockdown of Hif-1␣ reduced invasiveness of the tumor cells in vitro as well as extravasation and secondary infiltration in vivo. Liver metastases associated induction of proinvasive receptor tyrosine kinase Met phosphorylation as well as gelatinolytic activity were Hif-1␣-dependent. Indeed, promoter activity of the matrix metalloproteinase-9 (mmp-9) was shown to be Hif-1␣-dependent. This study uncovers a new survival-independent biological function of HIF-1␣ contributing to the efficacy of metastases formation.During the metastatic cascade, tumor cells encounter several kinds of microenvironmental stress, namely lack of oxygen and nutrients (1). Hypoxia-inducible factor-1 (HIF-1) 2 is a transcription factor known to mediate the adaptation to microenvironmental stress in general (2) as well as during tumor progression in particular (1). HIF-1 consists of a constitutively expressed ␤-subunit and a highly regulated ␣-subunit that is, under physiological conditions, degraded by the proteasome (3, 4). During stress situations such as hypoxia, HIF-1␣ is stabilized and translocates to the nucleus where it forms together with HIF-1␤ the heterodimeric transcription factor HIF-1 (5). Via its interaction with hypoxia-responsive elements, HIF-1 regulates the expression of molecules such as the major pH-regulating enzyme carbonic anhydrase IX (CAIX) (6), which allows the metabolic adaptation on the cellular level (7,8). Furthermore, HIF-1 signaling is also a major determinant of adaptation on the tissue level by induction of the "angiogenic switch," thereby overcoming the limited supply of oxygen and nutrients in expanding neoplasias (1).Recent findings led us to the hypothesis that HIF-1␣ not only impacts on metastasis formation by securing survival but also directly impacts on metastasis in a survival-independent manner. This hypothesis was based on the following findings. Reduced levels of HIF-1␣ correlate with decreased invasive potential of tumor cells in vitro (9 -11). HIF-1␣ knock-out reduced primary tumor onset and growth in a transgenic model of cancer initiation (12). This correlated with a later onset of pulmonary metastasis (12). Furthermore, constitutive expression of HIF-1␣ has been shown to enhance bone metastasis in a breast cancer model (13). Although these data have suggested that HIF-1␣ increases the metastatic potential of tumor cells, recent reviews by Bertout et ...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of a Survival-independent Metastasis-enhancing Role of Hypoxia-inducible Factor-1α with a Hypoxia-tolerant Tumor Cell Line

Schelter

Gerg

Halbgewachs

et al. 2010

Journal of Biological Chemistry

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“…Gelatinases are abundantly overexpressed in HCC and its stromal cells, and play an important role in tumor microenvironment (18,19). In this study, it found that the 'naked' fusion protein dFv-LDP had an inhibition rate of 38.8% at a dosage of 0.8 mg/kg in Bel-7402 xenograft, which indicated that the fusion protein dFv-LDP not only played as a carrier of AE, but also possessed certain antitumor efficacy in vivo.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activities of dFv-LDP-AE: An enediyne-energized fusion protein targeting tumor-associated antigen gelatinases

Zhong

Guo

et al. 2012

Oncology Reports

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Abstract.Gelatinases play an important role in tumor growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumors. Lidamycin is an enediyne antitumor antibiotic with potent cytotoxicity. We previously reported that a tandem scFv format (dFv-LDP-AE) showed enhanced binding ability with gelatinases compared with the scFv-lidamycin conjugate (Fv-LDP-AE). In this study, the antitumor activities of dFv-LDP-AE on hepatocellular carcinoma (HCC) were evaluated in vitro and in vivo. By SDS-PAGE analysis, it was found that partial fusion protein dFv-LDP existed as dimer; the results of ELISA and immunofluorescence demonstrated that the fusion protein dFv-LDP could efficiently bind to hepatoma cells in vitro. The apparent arrest of cell cycle at G2/M phase and induction of apoptosis at nanomole levels indicated that the dFv-LDP-AE was very potent against HCC. In in vivo experiments, dFv-LDP-AE shown enhanced cytotoxic effects compared to those of LDM. Administration at mouse tolerable dosage level, the inhibition rate of tumor growth was 89.5% of dFv-LDP-AE vs. 73.6% of LDM on transplantable H22 in mice (P<0.05) and, 87.3% of dFv-LDP-AE vs. 63.4% of LDM on hepatoma Bel-7402 in athymic mice (P<0.01). Small animal optical imaging showed that the FITC-labeled dFv-LDP preferentially localized in the tumor site in less than 30 min, which demonstrated remarkable tumor-targeting properties. Taken together with the above findings, the enediyne-energized fusion protein dFv-LDP-AE showed potential application as a new agent for therapeutic appications in HCC.

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“…Matrix Metallo-Proteinases (MMPs) are a family of enzymes involved in degradation of extracellular matrix (gelatinases, collagenases) and are vital in tissue remodeling during tumor invasion, metastasis, and angiogenesis. The MMP-9 (a member of the MMP family) is a known mediator of tumor cell invasion [146] and has recently been shown to be critical for the invasive steps of metastasis [147][148], the fact that its expression correlates with HIF-1α expression suggests that HIF-1α is involved in promoting MMP-9-dependent metastasis. As a result of this, we tested whether compounds could inhibit the expression of MMP-9 in MDA-MB-231 cells by western blot assay.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Breast Cancer Angiogenesis and Metastasis ay Targeting Hypoxia-Inducible Factor-1α

Madu¹

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DEDICATION"To (God) who is able to do immeasurably more than all we ask or imagine, according to his power that is at work within us"-Ephesians 3:20.And to my family-my wife, Pamela; and my children, Chinua and Elechi. For all you did to sustain my choice. Without you, this will not be.iv ACKNOWLEDGEMENTS I observe this dissertation today not as a completion of a search, but a celebration of success; symbolizing a temporary end as well as a beginning-signifying an achievement as well as triumph.This project culminating into this dissertation would not have been possible if it were not for the contributions and assistance I received from several people. In an attempt to express my appreciation, it will be very difficult to find words that have not already been used over again-a situation where statements will seem no longer sufficient and words inadequate. However I still wish to acknowledge the following persons who stood by me and contributed to make this long-nursed dream a reality.I would like thank my mentor, Dr Yi Lu, for the opportunity to work in his lab, and supervising this project. To my committee members, Dr Wei Li (for providing the compounds used in this project), Dr Leonard Lothstein (for his input, valuable discussions, and accessibility; for listening and reassuring), Dr Ram I Mahato (for his kind words of encouragement and permitting me to use his lab equipment), Dr Andrzej T Slominski (for his wise suggestions). Thank you for accepting to serve as members of this committee, your thoughtful criticism, and involvement during the course of this project. I would like to thank Dr liyuan Li for the lab training. I gratefully acknowledge Dr Pfeffer for his advice, and unending encouragement and support.My mother merits special thanks for her support and sacrifice through the years. So does my father-in-law, Obong Okon Mkpong, for his prayers and encouragement. Sufficient words fail me in expressing my gratitude to my wife, Eno-Obong Pamela, whose love, dedication, and relentless confidence in me was the driving force behind all of this. You are the bedrock upon which the past twelve years of my life have been built. My ambition was great, but your faith in me was greater. I love you dearly! To my children Chinua and Elechi, for their love, and understanding during the long years of my education, and sacrificially spending three summers with me in the lab-I promise, this is it! This project would never have been completed without the encouragement and devotion of all of you, and so many other family members and friends. In the words of President John F. Kennedy, "In your hands, more than mine, rest the final success of (my) course". Thank you! v ABSTRACTThe current clinical chemotherapy agents are not ideal for breast cancer as they are not curative, but only provide a modest extension of survival with sometimes a severely adverse effect on the patient's quality of life. There is, therefore, an urgent need to search for new and more effective anti-breast cancer drugs. However, the existing screening sy...

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Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Cited by 24 publications

References 56 publications

Identification of a Survival-independent Metastasis-enhancing Role of Hypoxia-inducible Factor-1α with a Hypoxia-tolerant Tumor Cell Line

Identification of a Survival-independent Metastasis-enhancing Role of Hypoxia-inducible Factor-1α with a Hypoxia-tolerant Tumor Cell Line

Antitumor activities of dFv-LDP-AE: An enediyne-energized fusion protein targeting tumor-associated antigen gelatinases

Inhibition of Breast Cancer Angiogenesis and Metastasis ay Targeting Hypoxia-Inducible Factor-1α

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