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Burmakin, M., van Wieringen, T., Olsson, P. O., Stuhr, L., Åhgren, A., Heldin, C.-H., . . . Hellberg, C. (2017). Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma. Journal of Translational Medicine, 15, Article ID 47.
Open this publication in new window or tab >>Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma
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2017 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, article id 47Article in journal (Refereed) Published
Abstract [en]

Background: Imatinib causes increased turnover of stromal collagen, reduces collagen fibril diameter, enhances extracellular fluid turnover and lowers interstitial fluid pressure (IFP) in the human colonic carcinoma KAT-4/HT-29 (KAT-4) xenograft model. Methods: We compared the effects of imatinib on oxygen levels, vascular morphology and IFP in three experimental tumor models differing in their content of a collagenous extracellular matrix. Results: Neither the KAT4 and CT-26 colonic carcinoma models, nor B16BB melanoma expressed PDGF beta-receptors in the malignant cells. KAT-4 tumors exhibited a well-developed ECM in contrast to the other two model systems. The collagen content was substantially higher in KAT-4 than in CT-26, while collagen was not detectable in B16BB tumors. The pO(2) was on average 5.4, 13.9 and 19.3 mmHg in KAT-4, CT-26 and B16BB tumors, respectively. Treatment with imatinib resulted in similar pO(2)-levels in all three tumor models but only in KAT-4 tumors did the increase reach statistical significance. It is likely that after imatinib treatment the increase in pO(2) in KAT-4 tumors is caused by increased blood flow due to reduced vascular resistance. This notion is supported by the significant reduction observed in IFP in KAT-4 tumors after imatinib treatment. Vessel area varied between 4.5 and 7% in the three tumor models and was not affected by imatinib treatment. Imatinib had no effect on the fraction of proliferating cells, whereas the fraction of apoptotic cells increased to a similar degree in all three tumor models. Conclusion: Our data suggest that the effects of imatinib on pO(2)-levels depend on a well-developed ECM and provide further support to the suggestion that imatinib acts by causing interstitial stroma cells to produce a less dense ECM, which would in turn allow for an increased blood flow. The potential of imatinib treatment to render solid tumors more accessible to conventional treatments would therefore depend on the degree of tumor desmoplasia.

Place, publisher, year, edition, pages
BioMed Central, 2017
Keyword
Hypoxia, Interstitial fluid pressure, Receptor tyrosine kinase, Tumor stroma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-320452 (URN)10.1186/s12967-017-1142-7 (DOI)000395566200004 ()28231806 (PubMedID)
Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2017-11-15Bibliographically approved
Bellomo, C., Caja, L., Fabregat, I., Mikulits, W., Kardassis, D., Heldin, C.-H. & Moustakas, A. (2017). Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma.. Cell Death and Differentiation.
Open this publication in new window or tab >>Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma.
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2017 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403Article in journal (Refereed) Epub ahead of print
Abstract [en]

Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-339262 (URN)10.1038/s41418-017-0021-3 (DOI)29230000 (PubMedID)
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-01-17
Mehić, M., de Sa, V. K., Hebestreit, S., Heldin, C.-H. & Heldin, P. (2017). The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function. Oncogenesis, 6, Article ID e348.
Open this publication in new window or tab >>The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function
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2017 (English)In: Oncogenesis, E-ISSN 2157-9024, Vol. 6, article id e348Article in journal (Refereed) Published
Abstract [en]

The levels of hyaluronan, a ubiquitous glycosaminoglycan prominent in the extracellular matrix, is balanced through the actions of hyaluronan-synthesizing enzymes (HAS1, 2 and 3) and degrading hyaluronidases (Hyal 1, 2, 3 and PH20). Hyaluronan accumulates in rapidly remodeling tissues, such as breast cancer, due to deregulated expression of the HAS2 gene and/or alterations of HAS2 activity. The activity of HAS2 is regulated by post-translational modifications, including ubiquitination. In order to identify deubiquitinating enzymes (DUBs) that are involved in de-ubiquitination of HAS2, a complementary (cDNA) library of 69 Flag-HA-tagged human DUBs cloned into retroviral vectors was screened in human embryonic kidney (HEK) 293T cells for their ability to de-ubiquitinate myc-tagged HAS2. Several DUBs were found to decrease the ubiquitination of 6myc-HAS2, among which, the most effective were USP17 and USP4. USP17 efficiently removed polyubiquitination, whereas USP4 preferentially removed monoubiquitination of 6myc-HAS2. Co-immunoprecipitation studies revealed interactions between HAS2 and USP17, as well as between HAS2 and USP4, in membrane preparations of HEK293T cells. USP17 significantly stabilized 6myc-HAS2 protein levels, whereas USP4 did not. The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis. Importantly, high levels of USP17 and HAS2 were detected in a panel of cancer cell lines compared to normal cells, and immunohistochemical stainings revealed higher expression of USP17 and HAS2 in tissues of lung cancer patients compared to normal tissue. In conclusion, USP17 and USP4 differently affect HAS2 ubiquitination, and the stability and function of HAS2.

Keyword
cell cycle, ubiquitination, DUBs, growth, hyaluronan, cancer
National Category
Cell and Molecular Biology
Research subject
Biology with specialization in Molecular Biology; Biochemistry
Identifiers
urn:nbn:se:uu:diva-312483 (URN)10.1038/oncsis.2017.45 (DOI)000406047300003 ()28604766 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-01-12 Created: 2017-01-10 Last updated: 2018-01-13Bibliographically approved
Okita, Y., Kimura, M., Xie, R., Chen, C., Shen, L.-W. T., Kojima, Y., . . . Kato, M. (2017). The transcription factor MAFK induces EMT and malignant progression of triple-negative breast cancer cells through its target GPNMB. Science Signaling, 10(474), Article ID eaak9397.
Open this publication in new window or tab >>The transcription factor MAFK induces EMT and malignant progression of triple-negative breast cancer cells through its target GPNMB
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2017 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 474, article id eaak9397Article in journal (Refereed) Published
Abstract [en]

Triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat. For example, the transforming growth factor-beta (TGF-beta) pathway is implicated in TNBC progression and metastasis, but its opposing role in tumor suppression in healthy tissues and early-stage lesions makes it a challenging target. Therefore, additional molecular characterization of TNBC may lead to improved patient prognosis by informing the development and optimum use of targeted therapies. We found that musculoaponeurotic fibrosarcoma (MAF) oncogene family protein K (MAFK), a member of the small MAF family of transcription factors that are induced by the TGF-beta pathway, was abundant in human TNBC and aggressive mouse mammary tumor cell lines. MAFK promoted tumorigenic growth and metastasis by 4T1 cells when implanted subcutaneously in mice. Overexpression of MAFK in mouse breast epithelial NMuMG cells induced epithelial-mesenchymal transition (EMT) phenotypes and promoted tumor formation and invasion in mice. MAFK induced the expression of the gene encoding the transmembrane glycoprotein nmb(GPNMB). Similar to MAFK, GPNMB overexpression in NMuMG cells induced EMT, tumor formation, and invasion, in mice, whereas knockdown of MAFK in tumor cells before implantation suppressed tumor growth and progression. MAFK and GPNMB expression correlated with poor prognosis in TNBC patients. These findings suggest that MAFK and its target gene GPNMB play important roles in the malignant progression of TNBC cells, offering potentially new therapeutic targets for TNBC patients.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321838 (URN)10.1126/scisignal.aak9397 (DOI)000398836400003 ()
Funder
Swedish Research Council, 2015-02757
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2017-05-15Bibliographically approved
Song, J., Mu, Y., Li, C., Bergh, A., Miaczynska, M., Heldin, C.-H. & Landstrom, M. (2016). APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain. OncoTarget, 7(1), 279-292.
Open this publication in new window or tab >>APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, p. 279-292Article in journal (Refereed) Published
Abstract [en]

The multifunctional cytokine transforming growth factor-beta (TGF beta) is produced by several types of cancers, including prostate cancer, and promote tumour progression in autocrine and paracrine manners. In response to ligand binding, the TGF beta type I receptor (T beta RI) activates Smad and non-Smad signalling pathways. The ubiquitin-ligase tumour necrosis factor receptor-associated factor 6 (TRAF6) was recently linked to regulate intramembrane proteolytic cleavage of the T beta RI in cancer cells. Subsequently, the intracellular domain (ICD) of T beta RI enters in an unknown manner into the nucleus, where it promotes the transcription of pro-invasive genes, such as MMP2 and MMP9. Here we show that the endocytic adaptor molecules APPL1 and APPL2 are required for TGF beta-induced nuclear translocation of T beta RI-ICD and for cancer cell invasiveness of human prostate and breast cancer cell lines. Moreover, APPL proteins were found to be expressed at high levels in aggressive prostate cancer tissues, and to be associated with T beta RI in a TRAF6-dependent manner. Our results suggest that the APPL-T beta RI complex promotes prostate tumour progression, and may serve as a prognostic marker.

Keyword
APPL proteins, prostate cancer, signal transduction, tumour necrosis factor receptor-associated factor 6, transforming growth factor beta
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-280903 (URN)10.18632/oncotarget.6346 (DOI)000369950300023 ()26583432 (PubMedID)
Funder
Swedish Cancer Society, 100303Swedish Cancer Society, ALF-VLL-224051The Kempe Foundations, SMK. 1132Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2017-11-30Bibliographically approved
Morikawa, M., Koinuma, D., Mizutani, A., Kawasaki, N., Holmborn, K., Sundqvist, A., . . . Miyazono, K. (2016). BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors. Stem Cell Reports, 6(1), 64-73.
Open this publication in new window or tab >>BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors
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2016 (English)In: Stem Cell Reports, ISSN 2213-6711, Vol. 6, no 1, p. 64-73Article in journal (Refereed) Published
Abstract [en]

Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Kruppel-like factors.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-276812 (URN)10.1016/j.stemcr.2015.12.004 (DOI)000368099500008 ()26771354 (PubMedID)
Funder
Swedish Cancer Society, 100452
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved
Carthy, J. M., Stoeter, M., Bellomo, C., Vanlandewijck, M., Heldin, A., Moren, A., . . . Moustakas, A. (2016). Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation. Scientific Reports, 6, Article ID 29868.
Open this publication in new window or tab >>Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 29868Article in journal (Refereed) Published
Abstract [en]

Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-301020 (URN)10.1038/srep29868 (DOI)000379878300001 ()27430378 (PubMedID)
Funder
Swedish Cancer Society, CAN 2006/1078, CAN 2009/900, CAN 2012/438Swedish Research Council, K2007-66X-14936-04-3, K2010-67X-14936-07-3, K2013-66X-14936-10-5EU, FP7, Seventh Framework Programme
Available from: 2016-08-17 Created: 2016-08-17 Last updated: 2017-12-05Bibliographically approved
Carthy, J. M., Engstrom, U., Heldin, C.-H. & Moustakas, A. (2016). Commercially Available Preparations of Recombinant Wnt3a Contain Non-Wnt Related Activities Which May Activate TGF- Signaling. Journal of Cellular Biochemistry, 117(4), 938-945.
Open this publication in new window or tab >>Commercially Available Preparations of Recombinant Wnt3a Contain Non-Wnt Related Activities Which May Activate TGF- Signaling
2016 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 117, no 4, p. 938-945Article in journal (Refereed) Published
Abstract [en]

The Wnt ligands are a family of secreted signaling proteins which play key roles in a number of cellular processes under physiological and pathological conditions. Wnts bind to their membrane receptors and initiate a signaling cascade which leads to the nuclear localization and transcriptional activity of -catenin. The development of purified recombinant Wnt ligands has greatly aided in our understanding of Wnt signaling and its functions in development and disease. In the current study, we identified non-Wnt related signaling activities which were present in commercially available preparations of recombinant Wnt3a. Specifically, we found that treatment of cultured fibroblasts with recombinant Wnt3a induced immediate activation of TGF- and BMP signaling and this activity appeared to be independent of the Wnt ligand itself. Therefore, while purified recombinant Wnt ligands continue to be a useful tool for studying this signaling pathway, one must exercise a degree of caution when analyzing the results of experiments that utilize purified recombinant Wnt ligands.

Keyword
BMP, SMAD, TGF-, Wnt3a, Wnt, FIBROBLAST
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-280221 (URN)10.1002/jcb.25378 (DOI)000370159900013 ()26369756 (PubMedID)
Available from: 2016-03-10 Created: 2016-03-09 Last updated: 2017-11-30Bibliographically approved
Moustakas, A. & Heldin, C.-H. (2016). Mechanisms of TGF beta-Induced Epithelial-Mesenchymal Transition. JOURNAL OF CLINICAL MEDICINE, 5(7), Article ID 63.
Open this publication in new window or tab >>Mechanisms of TGF beta-Induced Epithelial-Mesenchymal Transition
2016 (English)In: JOURNAL OF CLINICAL MEDICINE, ISSN 2077-0383, Vol. 5, no 7, article id 63Article, review/survey (Refereed) Published
Abstract [en]

Transitory phenotypic changes such as the epithelial-mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of adult tissues, and facilitate the progression of cancer. EMT can be induced by several extracellular cues in the microenvironment of a given epithelial tissue. One such cue, transforming growth factor beta (TGF beta), prominently induces EMT via a group of specific transcription factors. The potency of TGF beta is partly based on its ability to perform two parallel molecular functions, i.e. to induce the expression of growth factors, cytokines and chemokines, which sequentially and in a complementary manner help to establish and maintain the EMT, and to mediate signaling crosstalk with other developmental signaling pathways, thus promoting changes in cell differentiation. The molecules that are activated by TGF beta signaling or act as cooperating partners of this pathway are impossible to exhaust within a single coherent and contemporary report. Here, we present selected examples to illustrate the key principles of the circuits that control EMT under the influence of TGF beta.

Keyword
epithelial-mesenchymal transition, signal transduction, transcription factor, transforming growth factor beta, tumor invasiveness
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-300638 (URN)10.3390/jcm5070063 (DOI)000379369400004 ()
Available from: 2016-08-10 Created: 2016-08-10 Last updated: 2016-08-10Bibliographically approved
Watanabe, Y., Papoutsoglou, P., Maturi, V., Tsubakihara, Y., Hottiger, M. O., Heldin, C.-H. & Moustakas, A. (2016). Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation. Journal of Biological Chemistry, 291(24), 12706-12723.
Open this publication in new window or tab >>Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 24, p. 12706-12723Article in journal (Refereed) Published
Abstract [en]

We previously established a mechanism of negative regulation of transforming growth factor beta signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4. The positive role PARG plays during BMP signaling can be neutralized by PARP1, as demonstrated by experiments where PARG and PARP1 are simultaneously silenced. In contrast to PARG, ectopic expression of PARP1 suppresses BMP signaling, whereas silencing of endogenous PARP1 enhances signaling and BMP-induced differentiation. The two major Smad proteins of the BMP pathway, Smad1 and Smad5, interact with PARP1 and can be ADP-ribosylated in vitro, whereas PARG causes deribosylation. The overall outcome of this mode of regulation of BMP signal transduction provides a fine-tuning mechanism based on the two major enzymes that control cellular ADP-ribosylation.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-299724 (URN)10.1074/jbc.M116.729699 (DOI)000378119900024 ()27129221 (PubMedID)
Funder
Swedish Research Council, K2010-67X-14936-07-3 K2013-66X-14936-10-5
Available from: 2016-07-26 Created: 2016-07-26 Last updated: 2018-01-10Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9508-896x

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