TGF-β Meeting Report
Uppsala May 13-14, 2006
About 70 persons attended the TGF-β meeting, with representatives from the Branches in Uppsala, Melbourne and Brussels, as well as from the New York Office; in addition, members of the groups of Affiliates Drs. Kohei Miyazono (Tokyo University, Japan) and Peter ten Dijke (Leiden University Medical Center, Netherlands) and some of our outside collaborators participated. During the meeting, the participants listened to 42 presentations, and had ample time for interactions during coffee breaks, lunches and dinners. A lot of interesting data were presented and discussed. Some highlights are mentioned below.
The complexity of TGF-β signaling is constantly increasing and one of the most exciting aspects of this pathway is the identification of new regulators that are involved in tumor progression. Accordingly, Dr. Susumu Itoh (University of Tsukuba), reported on a newly identified gene target of the TGF-β pathway that is linked to various forms of malignancies, including colon, prostate, kidney, breast and ovarian cancer, and which is associated with the aggressive and metastatic behavior of such tumors. The Itoh group has now directly linked this protein to Smad signaling, as it binds to Smads and inhibits the early steps of TGF-β signal transduction. In a similar scenario, a novel mediator of epithelial-mesenchymal transition (EMT) downstream of TGF-β has been identified and was shown to lead to carcinoma metastasis, as reported by Dr. Annamaria Gal (Institute for Molecular Pathology, Vienna). The new pro-metastatic factor is a secreted cytokine that acts on epithelial cells and induces secretion of an array of chemokines, which secondarily enhance the metastatic response.
The tumor suppressor Smad4 plays a pivotal role in mediating anti-mitogenic and pro-apoptotic effects of TGF-β, but its function in TGF-β-induced invasion and metastasis has been unclear. Dr. ten Dijke reported on studies investigating the role of Smad4 in cellular and mouse models for TGF-β-induced breast cancer progression. Smad4 knockdown in breast cancer cells potently inhibited TGF-β-induced EMT. Furthermore, he showed that knockdown of Smad4 in MDA-MB-231 breast cancer cells inhibited the frequency of bone metastasis in nude mice by 75% and significantly increased metastasis-free survival. Communication of tumor cells with bone microenvironment appeared to be affected in Smad4 knockdown cells. Taken together, the results show that Smad4 plays an important role in breast cancer progression.
These exciting reports join those from the TGF-β Signaling Group of the Uppsala Branch on four novel gene targets of the TGF-β pathway that link to either the tumor suppressor or pro-metastatic action of this cytokine. These are transcription factors, as reported by Sylvie Thuault and Dr. Aristidis Moustakas, or signaling proteins, as reported by Hideki Niimi. In addition, a novel negative regulator of TGF-β signaling was reported by Peter Lönn. Finally, Katerina Pardali (Uppsala University) described a novel technique that couples antibody-based detection to DNA-based signal amplification, which may soon give us the opportunity to screen human tumor sections for activation of the TGF-β pathway with single-cell level of sensitivity.
Dr. Hong-Jian Zhu (Melbourne Branch) described a mechanism whereby overactivity of the epidermal growth factor receptor in tumors leads to suppression of TGF-β-induced growth inhibition, via activation of Stat3 and upregulation of Smad7. Another function of Smad7 was described by Dr. Maréne Landström (Uppsala Branch), i.e. as an adaptor to mediate activation of the Ser/Thr kinase TAK1 and the p38 MAP kinase pathway leading to apoptosis of prostate cancer cells.
Attendees at the TGF-β meeting held in Uppsala. Click here to see a larger version of this image.
Additional presentations from the Uppsala Branch, by Dr. Serhiy Souchelnytskyi, Anna Dubrovska, Hiruyki Iwahana, Nimesh Bhaskaran, and Aude Gautier, showed how proteomics can contribute to unveiling the complexity of TGF-β signaling. Proteomics-based profiling of phosphorylation, glycosylation and expression of proteins showed a number of novel signaling mechanisms in regulation of cell proliferation and apoptosis.
TGF-β in breast milk has been suggested to be a decisive factor in diminishing the risk of allergic diseases during infancy. By using an ovalbumin (OVA) food allergy model, Dr. Atsuhito Nakao (University of Yamanashi) reported that oral administration of high-dose TGF-β simultaneously with OVA feeding significantly inhibited the OVA-specific IgE elevation and anaphylactic reaction. Intra-peritoneal injection of anti-TGF-β-neutralizing antibody abolished the inhibitory effects of orally administered TGF-β on the suppression of anaphylactic reaction. He concluded that TGF-β, when taken orally at a high dose, has the capacity to modulate a food allergy-related reaction, at least in part, through its systemic activity.
Recent developments of studies of TGF-β signaling begin to deliver solutions that can be used for clinical applications. One such example was presented by Dr. Miyazono. Application of a low-molecular weight inhibitor of TGF-β type I receptor kinase and PEGylated adriamycin showed high efficacy in treatment of pancreatic adenocarcinoma and gastric cancer. The important finding is that this combination did not have any pronounced side effects, and that the molecular mechanism could involve an effect of the inhibitor on the microenvironment of the tumor cells, in addition to the direct effects on tumor cells themselves.
BMP signaling plays pivotal roles in homeostasis of blood vessels, and abnormalities in BMP type II receptor are known to be involved in pathogenesis of primary pulmonary hypertension. Dr. Yuka Suzuki (University of Tokyo), reported that BMP-4 stimulated the growth of endothelial cells derived from mouse embryonic stem cells (ESC). Since the expression and phosphorylation of Flk-1 and Tie-2 are induced by BMP-4, she concluded that BMP-4 induces the growth of ESC-derived endothelial cells through activation of VEGF-A/Flk-1 and Ang-1/Tie-2 signals. A presentation by Dr. Lia Pardali (Leiden University Medical Center) also addressed the role of TGF-β family members in vascular biology. She reported that the accessory receptor endoglin often is overexpressed in aggressive melanoma and Ewing sarcoma, and may contribute to vascular mimicry in these tumors.
Various growth factors, including VEGF-C, are known to play critical roles in lymphangiogenesis. Dr. Masako Oka (University of Tokyo) reported that TGF-β inhibited the proliferation and chemotaxis towards VEGF-C of human dermal lymphatic endothelial cells (HDLECs). Expression of a lymphatic endothelial cell marker Prox1 was repressed by TGF-β. In contrast, the low molecular weight TGF-β inhibitor, LY364947, stimulated the proliferation and chemotaxis to VEGF-C of HDLECs. She suggested that TGF-β signaling plays an important role in regulation of lymphangiogenesis.
In conclusion, the presentations at the meeting spanned from basic research on signaling mechanisms, to applied research on TGF-β antagonists in preclinical models. There is good hope that the research activities within the Program will unravel novel targets for the development of selective TGF-β antagonists, which will inhibit only the tumor progression effects of TGF-β, while leaving the tumor suppressive effects unperturbed.
Carl-Henrik Heldin (Director, Uppsala Branch)