TGF-beta signaling in cancer
Abstract
Transforming Growth Factor beta (TGF-beta) is a cytokine regulating a wide range of cellular processes such as proliferation, differentiation, and migration. At the early stages of cancer development TGF-beta functions as a tumor suppressor, mainly due to its inhibitory effect on cellular growth, but during cancer progression, mutations in TGF-beta signal components switches TGF-beta into a promoter of cancer cell proliferation, survival and metastasis.
The aim of this thesis was to study the role of TGF-beta signaling in the progression of two different cancer types - diffuse-type gastric carcinoma and neuroblastoma. Furthermore, we wanted to investigate the function in neuroblastoma of the nuclear receptor TLX, a protein involved in neuronal stem cell maintenance, and if TLX interacts with TGF-beta signaling.
We found that disruption of TGF-beta signaling in diffuse-type gastric carcinoma cells led to accelerated tumor growth in vivo through the induction of angiogenesis, possibly due to the repression of anti-angiogenic proteins including TIMP2. In addition, TGF-beta repressed expression of the cancer stem cell marker ABCG2 and diminished a subpopulation of cancer-initiating cells within the main cancer cell population, leading to reduced tumor formation.
TLX expression in neuroblastoma cells inhibited VHL-dependent degradation of HIF2-alpha, which then could bind and activate the VEGF promoter. Silencing of TLX induced VHL protein levels, reduced hypoxia-dependent induction of HIF2-alpha and inhibited cell proliferation. Furthermore, we found that TLX knockdown induced TGF-beta response in neuroblastoma cells as seen by increased TGF-beta dependent expression of its target genes p21 and Smad7. TLX physically interacts with Smad3 and knockdown of TLX led to increased TGF-beta dependent nuclear translocation of Smad2/3.
In conclusion, the results from this thesis suggest that TGF-beta signaling has an important tumor suppressive role in diffuse-type gastric carcinoma, due to both inhibition of tumor angiogenesis and repression of a cancer-initiating subpopulation of cancer cells. Furthermore, TLX was shown to be important for neuroblastoma cell proliferation, with a possible role in hypoxia-induced angiogenesis as well as in the regulation of TGF-beta signaling in neuroblastoma.
Parts of work
I. Johansson E, Komuro A, Iwata C, Hagiwara A, Fuse Y, Watanabe A, Morishita Y, Aburatani H, Funa K, Kano MR, Miyazono K. Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-beta-disrupted diffuse-type gastric carcinoma. Journal of Cancer Science 2010 Nov; 101(11):2398-2403
::doi::10.1111/j.1349-7006.2010.01688.x II. Ehata S, Johansson E, Katayama R, Koike S, Watanabe A, Hoshino Y, Katsuno Y, Komuro A, Koinuma D, Kano MR, Yashiro M, Hirakawa K, Aburatani H, Fujita N, Miyazono K. Transforming growth factor-beta decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. Accepted manuscript, Oncogene 2010 III. Zeng Z, Yoshida T, Johansson E, Lakshminarasimhan Chavali P, Hayashi A, Funa K. TLX controls angiogenesis through interaction with the Von Hippel-Lindau protein. Manuscript IV. Johansson E, Zeng Z, Yoshida T, Funa K. Nuclear receptor TLX inhibits TGF-beta signaling in neuroblastoma. Manuscript
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Biomedicine. Department of Medical Biochemistry and Cell Biology
Disputation
Måndagen den 6 december 2010, kl. 9.00, Hörsal Ragnar Sandberg, Medicinaregatan 5
Date of defence
2010-12-06
erik.johansson@medkem.gu.se
Date
2010-11-19Author
Johansson, Erik
Keywords
cancer
angiogenesis
TGF-beta
TLX
cancer stem cell
Publication type
Doctoral thesis
ISBN
978-91-628-8208-2
Language
eng