TGF-² Signaling Pathway in Lung Adenocarcinoma Invasion

Abstract

The histological distinction between bronchioloalveolar carcinoma (BAC) and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in non-mucinous BAC is significantly lower than that of pure invasive tumors and in tumors with greater than 0.6 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-ß (TGF-ß) signaling was identified as an important mediator of tumor invasion. Subsequent studies showed that the CC chemokine RANTES (Regulated on Activation, Normal T-cell Expressed, and presumably Secreted) was upregulated in invasive tumors and was required for invasion in cells with repressed levels of the TGF-ß type II receptor. Taken together, these studies illustrate how information gained from global expression profiling of tumors can be used to identify key pathways and genes mediating tumor growth, invasion, and metastasis.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…Ras pathway mutation classically activates growth factors including transforming growth factor beta (TGF-b), which induces ZEB1 mRNA, represses Pten mRNA and causes cell proliferation (Supplementary Fig. 6; refs [24][25][26]. Thus, release of growth factors such as TGF-b from K-Ras mutant tumours might be sufficient for ZEB1 induction, PTEN repression and proliferation of tumour-associated fibroblasts.…”

Effects of TGF-β signaling blockade on human A549 lung adenocarcinoma cell lines

“…Destruction of TGF-β signaling (especially TGFβRII) clearly induces tumorigenicity (28). However, tumors frequently lose their negative growth response to TGF-β and, in contrast, TGF-β signaling may promote tumor cell invasion and metastasis due to its ability to stimulate angiogenesis, alter the stromal environment, and significantly, cause local and systemic immunosuppression (8,(28)(29)(30)(31). Since it is still unclear as to whether TGF-β signaling plays a biological role in LAC progression, we focused on TGFβRII knockdown in LAC cells A549 to investigate the anti-tumor function of TGFβRII in vitro using RNA interference.…”

“…TGF-β binds to TGF-β receptor, type II (TGFβRII), which then phosphorylates and activates the type I receptor in the complex, and activates SMAD-dependent and -independent pathways. The non-SMAD signaling pathways are likely to mediate the positive effects on pro-carcinogenesis (6)(7)(8). Several investigators have reported that inactivation of the TGF-β signaling pathway reduces the ability of human cancer cells to progress (11)(12)(13)(14).…”

“…The transforming growth factor-β (TGF-β) signaling pathway has been shown to play a key role in carcinogenesis and cancer progression (6)(7)(8). NSCLC specimens overexpress TGF-β, which has been detected by multivariate analysis to be an independent risk factor for pulmonary metastasis and correlates with decreased survival (9)(10).…”

The transforming growth factor beta-1 in the oncogenesis of human lung adenocarcinoma

“…Действитель-но, при НМРЛ -наиболее распространенном гисто-логическом подтипе РЛ с высоким уровнем смертно-сти -увеличение экспрессии TGF-β1 коррелирует с прогрессией опухоли и плохой выживаемостью па-циентов. Различные экспериментальные модельные системы подтверждают мнение о прометастатической роли TGF-β1 в этих опухолях [22][23][24][25]. Тем не менее одной из основных нерешенных задач остается иден-тификация генов-мишеней для TGF-β1, которые управляют различными стадиями метастазирования, тем более что TGF-β1 модулирует экспрессию генов по-разному в зависимости от типа клеток [26,27].…”