The Role of Transforming Growth Factor-β in Tumor Metastasis

Stav Cullum

Introduction. Epithelial-mesenchymal transition (EMT) is a process by which cells lose epithelial and gain mesenchymal characteristics, allowing migration for physiological (development) or pathological (metastatic) purposes.1 Once a tumor cell loses expression of cellular adhesion protein E-cadherin, it is capable of invading the extracellular matrix and vascular dissemination.2,7 It has been hypothesized that metastasis occurs through highly migratory, mesenchymal-like single cells in a primary tumor site.2 However, new data contrasts this hypothesis and suggests EMT occurs in circulation through an interaction between circulating tumor cells (CTCs), the release of transforming growth-factor β (TGF-β) by platelets, and subsequent induction of EMT.2 Methods. To determine the role(s) of TGF-β in EMT, an in-silico model was constructed.3 Findings were confirmed in murine and human liver cancer models. Another study measured the abundance of proteins, mRNAs and microRNAs representing core regulators of EMT in a human mammary epithelial cell line.5 Additionally, CTCs were obtained using microfluidic capture with epithelial and tumor-specific antibodies.2 The EMT state of these CTCs was then analyzed using RNA-in situ hybridization (ISH). Results. The in-silico model showed TGF-β is a major signal for EMT induction.3 Additionally, activation of EMT showed repressed transcription of E-cadherin in murine and human epithelial cell lines. Increasing concentrations of TGF-β in the human cell line resulted in transition to a mesenchymal state.5 RNA expression analysis supported a two-step EMT, with each step associated with abrupt increase in a transcription factor (TF) and reduction in the corresponding inhibitory miRNA.5 The data suggest TF SNAIL1 is involved in the first step, and TF ZEB1 in the second. Interestingly, two markers of mesenchymal cells, N-cadherin and vimentin, are promoted by SNAIL1 and ZEB1. RNA ISH detected hybrid biphenotypic epithelial/mesenchymal cells and clusters of CTCs strongly expressed mesenchymal markers in comparison to single migratory cells.2 Finally, when stained with CD61 marker for platelets, CTCs were abundantly positive and RNA transcripts in these cells showed a strong TGF-β signature.2 Conclusions. New data suggests metastasis may occur through the proliferation of a single cell that has undergone EMT in a CTC.2 Additionally, given the critical role of TGF-β in EMT, inhibiting components of its signaling pathway has potential as anti-metastatic therapy.1-6 Further research embodies significant clinical relevance, as a high level of TGF-β has shown to be an important prognostic indicator of shorter overall survival in cancer.6

 

  1. Steinway SN, Zanudo JGT, Michel PJ, Feith DJ, Loughran TP, Albert R. Combinatorial interventions inhibit TGFbeta-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes. NPJ systems biology and applications. 2015;1:15014.
  2. Yu M, Bardia A, Wittner BS, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science (New York, NY). 2013;339(6119):580-584.
  3. Steinway SN, Zanudo JG, Ding W, et al. Network modeling of TGFbeta signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint sonic hedgehog and Wnt pathway activation. Cancer research. 2014;74(21):5963-5977.
  4. Steinway SN, Zanudo JGT, Michel PJ, Feith DJ, Loughran TP, Albert R. Combinatorial interventions inhibit TGFbeta-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes. NPJ systems biology and applications. 2015;1:15014.
  5. Zhang J, Tian XJ, Zhang H, et al. TGF-beta-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Science signaling. 2014;7(345):ra91.
  6. Peng L, Yuan XQ, Zhang CY, et al. High TGF-beta1 expression predicts poor disease prognosis in hepatocellular carcinoma patients. Oncotarget. 2017;8(21):34387-34397.
  7. Strilic B, Offermanns S. Intravascular Survival and Extravasation of Tumor Cells. Cancer cell. 2017;32(3):282-293.