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Abstract

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References

The Fujihara International Seminar series is supported by the Fujihara Foundation for Science, for the purpose of organizing seminars for basic and applied science, including medical science, physics, chemistry, engineering, mathematics, geology, and biology. The 59th Fujihara International Seminar was held on July 14–17, 2010 at Tomakomai, Hokkaido, Japan, focusing on molecular mechanisms of transforming growth factor (TGF)-β signaling and disease. Recent findings on mechanisms of TGF-β signaling, the roles of TGF-β signaling in carcinogenesis and progression of tumors, and possible strategies of TGF-β-based treatment of cancer were discussed at the seminar. In particular, novel mechanisms of regulation of Smad signaling, the differential roles of Smad proteins in carcinogenesis, function of Smads in regulation of microRNA biogenesis, and treatment of cancer stem cells by targeting the TGF-β signaling pathways were discussed. (Cancer Sci 2011; 102: 1242–1244)

Transforming growth factor (TGF)-β is a multifunctional cytokine, and shows a wide variety of activity on various cells. It is well known that TGF-β shows potent growth inhibitory activity on most types of cells, such as epithelial cells, endothelial cells, and lymphocytes. In addition, TGF-β has been shown to induce epithelial–mesenchymal transition, leading to the facilitation of migration and invasion of cancer cells.(1) The biological effects of TGF-β on cancer are thus bi-directional; TGF-β acts as an anti-oncogenic factor by inhibition of epithelial cell growth, while it functions as a pro-oncogenic factor through induction of epithelial–mesenchymal transition and other effects.

Transforming growth factor-β belongs to a large family of cytokines known as the TGF-β family, which includes activin, myostatin, and the bone morphogenetic proteins (BMPs). Most of the TGF-β family proteins bind to two distinct types of serine-threonine kinase receptors, known as type I and type II, which activate intracellular signaling molecules, including Smad proteins.(2) They then phosphorylate receptor-regulated Smads (R-Smads), which form complexes with common-partner Smad (co-Smad) and regulate the transcription of target genes in the nucleus. Smad2 and Smad3 are R-Smads activated by TGF-β, whereas Smad4 is the only co-Smad in mammals. Inhibitory Smads are the third type of Smads, and inhibit signaling by the TGF-β family proteins.

International meetings focusing on TGF-β family signaling have been held on various occasions. In Japan, we organized the 28th Sapporo Cancer Seminar on “TGF-β Signaling and Cancer” in 2008.(3) Due to the rapid progress in the field and the accumulation of enormous numbers of new findings, especially concerning the mechanisms of TGF-β signaling and its roles in the invasion of cancer and regulation of cancer stem cells, we decided to organize an international meeting to enable discussion of the mechanisms of TGF-β signaling and its relationship to disease. We invited 20 researchers from Sweden, the Netherlands, the USA, China, Korea, and Japan as speakers. More than 80 scientists participated in the seminar, and 28 posters were presented at the poster sessions (Fig. 1). The program of the seminar is available on-line (http://fis59.umin.jp/).

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Figure 1.  Participants of the 59th Fujihara International Seminar.

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Session 1: Molecular mechanisms of TGF-β family signaling

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References

After opening remarks and an introduction on the morning of July 15, Carl-Henrik Heldin (Uppsala, Sweden), Mitsuyasu Kato (Tsukuba, Japan), Aristidis Moustakas (Uppsala, Sweden), Keiji Miyazawa (Yamanashi, Japan), Xin-Hua Feng (Houston, TX, USA and Zhejiang, China), and Rosemary Akhurst (San Francisco, CA, USA) presented their findings on molecular mechanisms of TGF-β family signaling.

Transforming growth factor-β family signaling is regulated both positively and negatively through various mechanisms. The functions of inhibitory Smads and c-Ski/SnoN, in particular, have been extensively studied.(2,4) Inhibitory Smads, including Smad7, directly interact with type I receptors and compete with R-Smads for receptor activation, whereas c-Ski and SnoN serve as transcriptional co-repressors in the nucleus. The amplitude and duration of TGF-β signaling are fine-tuned by such negative regulators, which often form negative-feedback loops initiated by signal activation. Aristidis Moustakas presented findings indicating the salt-inducible kinase (SIK) negatively regulates TGF-β signaling together with Smad7. Salt-inducible kinase forms a complex with Smad7 and downregulates the expression of activated TGF-β type I receptor (TβRI) through ubiquitin-dependent degradation. He showed that SIK contains the kinase and ubiquitin-associated domain, and that both of these domains are required for the degradation of TβRI protein.

Mitsuyasu Kato showed that transmembrane prostate androgen induced RNA (TMEPAI) inhibits TGF-β signaling by suppression of R-Smad activation by TβRI. TMEPAI interacts with R-Smads and competes with SARA (Smad anchor for receptor activation) for R-Smad binding, resulting in sequestration of R-Smads from activation by the TβRI kinase. Similar to inhibitory Smads and Ski/SnoN, expression of TMEPAI is induced by TGF-β signaling. Moreover, the TMEPAI promoter is regulated by TGF-β-Smad signaling as well as by Wnt-β-catenin-TCF7L2 signaling. These findings indicate that TGF-β signaling is negatively regulated by multiple mechanisms in cells, and that it controls the magnitude and duration of TGF-β signaling under both physiological and pathological conditions.

Session 2: TGF-β signaling and cancer

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References

In the afternoon session of 15 July, Xiao-Fan Wang (Durham, NC, USA), Kunxin Luo (Berkeley, CA, USA), Takeshi Imamura (Tokyo, Japan), and Xiao-Jing Wang (Denver, CO, USA) discussed TGF-β signaling and cancer.

Perturbations of TGF-β signaling are observed in many malignancies, including head and neck squamous cell carcinoma (HNSCC).(5) Xiao-Jing Wang showed that Smad4 is frequently downregulated not only in HNSCC malignant lesions but also in normal adjacent mucosa. Her group generated mice in which Smad4 was deleted in head and neck epithelia, and found that the mice spontaneously developed HNSCC. She further showed a connection between Smad4 and the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility. She also presented findings that mice with keratinocyte-specific knockout of Smad2 showed increased susceptibility to squamous cell carcinomas, and that they showed increase in angiogenesis through overexpression of hepatocyte growth factor (HGF) in epithelial cells and activation of the HGF receptor c-Met in endothelium. Importantly, loss of Smad2 caused upregulation of HGF through loss of Smad2-induced transcriptional repression and enhanced transcriptional activation by the Smad3/Smad4 complex, which is bound to the transcriptional coactivator CBP/p300. As Smad2 expression is often downregulated in human squamous cell carcinomas, blockade of HGF-c-Met signaling may be useful for treatment of Smad2-deficient squamous cell carcinomas.

Session 3: TGF-β signaling and vascular, bone, and other diseases

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References

In the morning session of 16 July, Rik Derynck (San Francisco, CA, USA), Hideyuki Beppu (Toyama, Japan), Ye-Guang Chen (Beijing, China), Akiko Hata (Boston, MA, USA), and Peter ten Dijke (Leiden, The Netherlands) presented their recent findings on TGF-β signaling and vascular and other diseases.

MicroRNAs (miRNAs) constitute a class of ∼22 nucleotide non-coding RNAs. miRNAs regulate a wide variety of biological functions by inducing the degradation or inhibiting the translation of target mRNAs.(6) Akiko Hata showed that TGF-β and BMPs induce a contractile phenotype in vascular smooth muscle cells by miR-21. Transforming growth factor-β and BMP signaling stimulates rapid increase in the expression of mature miR-21 by facilitating the processing of primary transcripts of miR-21 (pri-miR-21) to precursor miR-21 (pre-miR-21) by Drosha. In contrast to transcriptional activation by Smads, R-Smads, but not co-Smad (Smad4), are required for the upregulation of pre-miR-21 and mature miR-21 upon ligand stimulation. Furthermore, her group identified 20 miRNAs regulated by TGF-β/BMP and found that a majority of these miRNAs contain a consensus sequence (termed R-SBE) within the stem region. She showed that R-Smads directly bind to the R-SBE and post-transcriptionally regulate miRNA processing through binding to the pri-miRNA.

Session 4: Implications in TGF-β-based therapies

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References

In the morning session of 17 July, Seong-Jin Kim (Incheon, Korea), S. Paul Oh (Gainesville, FL, USA), Makoto Mark Taketo (Kyoto, Japan), Atsushi Hirao (Kanazawa, Japan), and H.Q. Han (Thousand Oaks, CA, USA) presented their findings regarding the implications of TGF-β-based therapies.

The concept of “cancer stem cells” is an attractive explanation for the functional heterogeneity of cancer cells observed in many types of tumors.(7) Indeed, stem-like cells are now believed to be responsible for sustaining tumor growth and resistance to conventional therapies, and are thus ideal targets of cancer treatment.

Atsushi Hirao previously reported that a forkhead transcription factor, Foxo3a, which acts downstream of the PI3 kinase-Akt signaling pathway, is important for self-renewal of hematopoietic stem cells. In this seminar, he showed the roles of Foxo3a in the regulation of leukemia stem cells. Bcr-Abl encodes a constitutively active tyrosine kinase that is responsible for the pathogenesis of CML. Bcr-Abl activates PI3 kinase-Akt signaling, leading to nuclear export of Foxo3a and inhibition of its transcriptional activity. However, Foxo3a plays an essential role in the maintenance of leukemia stem cells in CML, and activity of Akt is suppressed in these cells. Interestingly, he showed that TGF-β regulates the localization of Foxo3a and activation of Akt in leukemia stem cells. He also presented findings that the combination of treatment with TGF-β inhibitor, Foxo3a deficiency, and use of imatinib (an inhibitor of Bcr-Abl) leads to efficient depletion of CML in vivo, indicating the critical role of the TGF-β-FOXO pathway in the maintenance of leukemia stem cells in CML.

Conclusion

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References

The 59th Fujihara International Seminar was successful in two respects. First, there were many excellent talks and fruitful discussion. I have introduced only some of the presentations in this report, and many other novel findings were presented in the seminar. I should add here that understanding the roles of TGF-β family signaling in cancer will enable the clinical use of drugs that directly or indirectly regulate TGF-β family signaling. H.Q. Han (Amgen Research) has shown the effectiveness of the soluble activin type IIB receptor in treating cancer cachexia in several animal models; this finding was published just after the seminar.(8) His finding suggests that not only regulation of TGF-β signaling but also that of other TGF-β family members may be used for cancer treatment in the future. Second, in addition to participants from Japan, the USA and Europe, 18 researchers from Korea and China participated in this seminar and discussed their recent findings. Some laboratories in Korea and China are focusing research on TGF-β family signaling, and researchers from these laboratories presented their findings at this seminar. I do hope that collaboration between these laboratories will lead to some interesting discoveries in the future. I believe that all participants had fruitful discussion at this seminar, and enjoyed their stay in Tomakomai.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References

The seminar organizers gratefully acknowledge the following grants: the Fujihara Foundation of Science, Core-to-Core Program, and the Global Center of Excellence Program for Integrative Life Science Based on the Study of Biosignaling Mechanisms (University of Tokyo) of the Japan Society for the Promotion of Science.

References

  1. Top of page
  2. Abstract
  3. Session 1: Molecular mechanisms of TGF-β family signaling
  4. Session 2: TGF-β signaling and cancer
  5. Session 3: TGF-β signaling and vascular, bone, and other diseases
  6. Session 4: Implications in TGF-β-based therapies
  7. Conclusion
  8. Acknowledgments
  9. References