Role Of TGFβ In Cancer Research Articles

Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment.

TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies.

Towards the contribution of the p38MAPK pathway to the dual role of TGFβ in cancer: A boolean model approach

The transforming growth factor-beta (TGF-β) pathway is involved in the regulation of cell growth and differentiation. In normal cells or in the early stages of cancer, this pathway can control proliferation stimuli by inducing cell cycle arrest or apoptosis (through the MAP-kinase protein p38MAPK), while in late stages it seems to act as a tumor promoter. This feature is known as the TGF-β dual role in cancer and it is not completely explained. This seems to arise through the accumulation of mutations in cancer development that affect the normal function of these pathways. In this work we propose a Boolean model of the crosstalk between the TGF-β, p38 MAPK and cell cycle checkpoint pathways which qualitatively describes this dual behavior. The model shows that for the wild type case, TGF-β acts as tumor supressor by inducing cell cycle arrest or apoptosis, as expected. However, the loss of function (LoF) of its two signaling proteins: SMAD2 and SMAD3 has immortalization effects due to the activation of the PI3K/AKT pathway that contributes to inhibit apoptosis. In silico mutations of the model elements were compared with cell phenotypes in experiments presenting agreement. In addition, we performed a series of double gene perturbations (that simulate random deleterious mutations) to determine the main regulators of the network. The results suggest that SMAD2/3 and p38MAPK are key players in processing the network input. In addition, when the LoF of SMAD2/3 is combined with the LoF of p38MAPK and p53, cell cycle arrest is completely abrogated. In conclusion, the model allows to visualize, through in silico mutations, the dual role of TGF-β: for the wild-type case TGF-β is able to block proliferation, however deleterious mutations can impair cell cycle arrest promoting cellular proliferation.

Abstract 955: LY3200882, a novel, highly selective TGFβRI small molecule inhibitor

Abstract The transforming growth factor β (TGFβ) signaling pathway is a pleiotropic cellular pathway that plays a critical role in cancer. In fact, aggressive tumors are typically associated with high ligand levels and thus associated with poor prognosis in various tumor types. Cancer cells use autocrine and paracrine TGFβ signaling to modulate tumor cells and the tumor microenvironment leading to a highly invasive and metastatic phenotype, inducing and increasing tumor vascularization, modulating the extracellular matrix in the stroma, and inhibiting immune surveillance and antitumor immunity. Clinical studies with galunisertib (aka LY2157299 monohydrate), a small molecule inhibitor targeting the TGFβ pathway, have provided proof of concept data supporting the role of TGFβ in cancer and the utility of targeting the TGFβ pathway. Here we describe the identification of LY3200882, a next generation small molecule inhibitor of TGF-β receptor type 1 (TGFβRI). The molecule is a potent, highly selective inhibitor of TGFβRI embodied in a structural platform with a synthetically scalable route. It is an ATP competitive inhibitor of the serine-threonine kinase domain of TGFβRI. Mechanism of action studies reveal revealed that LY3200882 inhibits various pro-tumorigenic activities. LY3200882 potently inhibits TGFβ mediated SMAD phosphorylation in vitro in tumor and immune cells and in vivo in subcutaneous tumors in a dose dependent fashion. In preclinical tumor models, LY3200882 showed potent anti-tumor activity in the orthotopic 4T1-LP model of triple negative breast cancer and this activity correlated with enhanced tumor infiltrating lymphocytes in the tumor microenvironment. Durable tumor regressions in the orthotopic 4T1-LP model were observed and rechallenge of congenic tumors resulted in complete rejection in all mice. In in vitro immune suppression assays, LY3200882 has shown the ability to rescue TGFβ1 suppressed or T regulatory cell suppressed naïve T cell activity and restore proliferation. Therefore, LY3200882 shows promising activity as an immune modulatory agent. In addition, LY3200882 has shown anti-metastatic activity in vitro in migration assays as well as in vivo in an experimental metastasis tumor model (intravenous EMT6-LM2 model of triple negative breast cancer). Finally, LY3200882 shows combinatorial anti-tumor benefits with checkpoint inhibition (anti-PD-L1) in the syngeneic CT26 model. In conclusion, we have developed a novel potent and highly selective small molecule inhibitor of TGFβRI for the treatment of cancer. Citation Format: Huaxing Pei, Saravanan Parthasarathy, Sajan Joseph, William McMillen, Xiaohong Xu, Stephen Castaneda, Ivan Inigo, Karen Britt, Bryan Anderson, Gaiying Zhao, Scott Sawyer, Douglas Beight, Talbi Kaoudi, Chandrasekar Iyer, Huimin Bian, Amy Pappas, David Surguladze, David Schaer, Karim Benhadji, Michael Kalos, Kyla Driscoll. LY3200882, a novel, highly selective TGFβRI small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 955. doi:10.1158/1538-7445.AM2017-955

Abstract LB-202: 14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2

Abstract TGF-β manifests multifunctional and dichotomous roles in different stages of cancer progression. In premalignant cells, TGF-β is primarily a tumor suppressor that inhibits cell proliferation or induces apoptosis. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by inducing epithelial-mesenchymal transition (EMT), leading to increased invasion of cancer cells, and also by inducing genes that facilitate metastatic colonization of secondary organ sites. Although the opposing functions of TGF-β in early- versus late-stage cancer have been known for decades, how and when TGF-β switches its functional roles are long-standing questions with no clear answer. It has been postulated that the dichotomous functions of TGF-β are dictated by different partners of its downstream Smads. However, it is unclear how Smad partners are changed in different stages of cancer. We have investigated how Smad partners are changed in different stages of breast cancer development in 2D and 3D cell cultures by both hypothesis-driven and unbiased approaches, in mouse models of bone metastasis, by bioinformatics analysis of breast cancer TCGA data, and by immunohistochemistry analysis of different stages of human breast diseases/cancers. Together, our data demonstrated that 14-3-3ζ overexpression induces contextual changes of Smad partners. Specifically, 14-3-3ζ 1) switches off TGF-β's cytostatic tumor suppressor function during the early stage (ADH) of breast cancer development by cytoplasmic sequestration of YAP1, leading to reduced 14-3-3σ transcription, which results in destabilization of p53, a Smad determinant for p21 transactivation in pre-malignant cells, and consequently decreased p21 expression; 2) switches on TGF-β's metastasis promoter function during breast cancer progression (DCIS/IDC) by blocking Gli2 binding with its E3 ligase β-TrCP, thus stabilizing Gli2, a Smad determinant for PTHrP transactivation in cancer cells, leading to bone metastasis (Cancer Cell, In Press, 2015). The critical role of TGF-β in cancer, especially in the process of metastasis, has spurred the development of TGF-β-targeting agents as cancer therapeutics. Disappointingly, many of the current TGF-β-targeting drugs showed limited clinical efficacy. Considering the opposing functions of TGF-β in cancer development, general inhibition of the TGF-β pathway may have deleterious consequence. Based on our new findings, the 14-3-3ζ-driven contextual changes of Smad partners from p53 to Gli2 may serve as a) biomarkers and b) therapeutic targets of TGF-β-mediated cancer progression and metastasis. Citation Format: Jia Xu, Sunil Acharya, Ozgur Sahin, Lin Zhang, Frank J. Lowery, Aysegul A. Sahin, Xiang H.-f. Zhang, Mien-Chie Hung, Dihua Yu. 14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-202. doi:10.1158/1538-7445.AM2015-LB-202

The microRNA networks of TGFβ signaling in cancer

In metazoans, the transforming growth factor β (TGFβ) signaling regulates a host of activities ranging from embryonic development to tissue homeostasis. The normal as well as tumor cells respond to this cytokine signaling pathway in a highly context-dependent manner. It acts as a potent tumor suppressor initially by inducing cell cycle arrest and apoptosis. But advanced tumors often misuse TGFβ signaling for tumor progression by selectively disabling the tumor suppressor arm and using other properties of TGFβ signaling such as induction of angiogenesis, epithelial to mesenchymal transition, and metastases. This dual role of TGFβ in cancer remained a mystery until recently. But recent advances in the field of microRNA provided a deeper understanding about this dual nature of TGFβ signaling in cancers. In the present review, we present an account of the role of microRNAs in deregulating TGFβ signaling and modulating cancer cell behavior during tumor initiation and cancer progression. This review also includes a discussion on the recent advances in the deregulation of TGFβ signaling in carcinogenesis.

Molecular Pathways: Targeting the TGF-β Pathway for Cancer Therapy

TGF-β is a ubiquitous cytokine that plays an active role in many cellular processes. Nearly every cell type has the ability to secrete TGF-β, as well as the ability to respond to TGF-β via the presence of TGF-β receptors on the cell surface. Consequently, gain or loss of function of the TGF-β pathway and its components are known to lead to a variety of diseases, including cancer. In epithelial cells, TGF-β functions as a tumor suppressor, where it inhibits proliferation, induces apoptosis, and mediates differentiation. Conversely, in other contexts, TGF-β promotes tumor progression through increasing tumor cell invasion and metastasis. Thus, TGF-β can have opposing roles, likely dependent, in part, on whether the cancer is early or late stage. The effects of TGF-β on tumor suppression and promotion are not limited to the tumor cell itself; rather, these effects can also be mediated through the stroma and the immune system. The dichotomous role of TGF-β in cancer highlights our need to understand the contextual effects of this cytokine to better guide patient selection for the use of anti-TGF-β therapies currently in clinical trials.

Transforming growth factor-beta: A target for cancer therapy

Transforming growth factor-beta (TGF-β) is a pleiotropic growth factor that regulates cell growth and differentiation, apoptosis, cell motility, extracellular matrix production, angiogenesis, and cellular immune responses. TGF-β demonstrates paradoxical action whereby it can function to suppress early tumorigenesis; however, it can also facilitate malignant transformation and stimulate tumor growth by manipulating a more hospitable environment for tumor invasion and the development of metastases. Given the integral role of TGF-β in transformation and cancer progression, various components of the TGF-β signaling pathway offer potentially attractive therapeutic targets for cancer treatment. This review focuses on the role of TGF-β in cancer and discusses both small and large molecule drugs currently in development that target TGF-β, its receptor and important down stream steps along its signaling pathway.