Antimetastatic Role of Smad4 Signaling in Colorectal Cancer

Zhang, Bixiang; Halder, Sunil K.; Kashikar, Nilesh; Cho, Yong-Jig; Datta, Arunima; Gorden, D. Lee; Datta, Pran K.

doi:10.1053/j.gastro.2009.11.004

Cited by 201 publications

(171 citation statements)

References 21 publications

(37 reference statements)

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“…Our results are further confirmed by the observation that in addition to loss of P53, SMAD4 inactivation plays a key role in late stages of CRC, such as migration and metastatic outgrowth potential. SMAD4 inactivation appeared to block differentiation, which is in line with previous findings where SMAD4 loss was associated with cell spreading, liver metastasis, and a poor disease prognosis (2,(20)(21)(22)(23). Together, our study depicts metastasis as an extremely inefficient process where at least four genetic alterations are required for tumor cells to seed and grow out at distant sites independently of stem cell niche factors.…”

Section: Discussionsupporting

confidence: 79%

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

Fumagalli

Drost

Suijkerbuijk

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

204

190

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In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize-i.e., to colonize distant sites-is the direct consequence of the loss of dependency on specific niche signals.colorectal cancer | adenoma-carcinoma sequence | organoids | metastasis | niche independence

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Section: Discussionsupporting

confidence: 79%

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

Fumagalli

Drost

Suijkerbuijk

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

204

190

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“…Therefore, crosstalk between Smad and the non-Smad pathway plays a critical role in regulating tumor progression, although the exact mechanism of this crosstalk remains elusive. We previously showed that Smad4 overexpression reverses TGF-β from a tumor promoter to a tumor suppressor (10). In the present study, we identified that Smad4 deficiency in CT26 cells induced tumor progression in vivo and in vitro.…”

Section: Discussionsupporting

confidence: 49%

“…The liver metastasis model was established by splenic injection of CT26 cells in BALB/c mice as previously described (10). Liver metastases were removed 4 weeks after cell inoculation and cut into small pieces in phosphate-buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

“…on a 3 times/week basis for three consecutive weeks, and for CT26 allografts, 5-FU (100 mg/kg) was administered once a week during the first two weeks and 50 mg/kg once a week thereafter as previously described (13,14). Tumor volume was calculated as previously described (10) ) in 100 µl serum-free media were seeded to the upper chamber of 8-µm pore Transwells coated with collagen. Cells were allowed to migrate towards 10% FBS containing medium in the lower chamber for 5 h. Cells on the upper side of the membrane were removed with a cotton swab.…”

Section: Methodsmentioning

confidence: 99%

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Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

Zhang

Leng

et al. 2015

Oncology Reports

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Abstract. 5-Fluorouracil (5-FU), a cell cycle-specific antimetabolite, is one of the most commonly used chemotherapeutic agents for colorectal cancer (CRC). Yet, resistance to 5-FU-based chemotherapy is still an obstacle to the treatment of this malignancy. Mutation or loss of Smad4 in CRC is pivotal for chemoresistance. However, the mechanism by which Smad4 regulates the chemosensitivity of CRC remains unclear. In the present study, we investigated the role of Smad4 in the chemosensitivity of CRC to 5-FU, and whether Smad4-regulated cell cycle arrest is involved in 5-FU chemoresistance. We used Smad4-expressing CT26 and Smad4-null SW620 cell lines as experimental models, by knockdown or transgenic overexpression. Cells or tumors were treated with 5-FU to determine chemosensitivity by cell growth, tumorigenicity assay and a mouse model. Cell cycle distribution was examined with flow cytometric analysis, and cell cycle-related proteins were examined by western blotting. Smad4 deficiency in CT26 and SW620 cells induced chemoresistance to 5-FU both in vitro and in vivo. Smad4 deficiency attenuated G1 or G2 cell cycle arrest by activating the PI3K/Akt/CDC2/survivin pathway. The PI3K inhibitor, LY294002, reversed the activation of the Akt/CDC2/survivin cascade in the Smad4-deficient cells, while it had little effect on cells with high Smad4 expression. In conclusion, we discovered a novel mechanism mediated by Smad4 to trigger 5-FU chemosensitivity through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade. The present study also implies that LY294002 has potential therapeutic value to reverse the chemosensitivity of CRC with low Smad4 expression.

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“…This function may be correlated with the decreased expression of TβR I, TβR II and common-mediator Smads (Smad4), which limit the downward propagation of the TGF-β1/Smad4 signal and subsequently cause tumor growth inhibition to reduce or even become deficient. Certain animal experiments and clinical studies (28)(29)(30)(31) have also revealed that, within the tumor, several types of mutations in the TβR II and Smad4 genes have been identified. The loss of TβR II function may cause tumor cells to deregulate the expression of the receptor protein, obstruct the transmission of the TGF-β1 growth inhibiting signal (32) and subsequently display malignant proliferation and invasion.…”

Section: Discussionmentioning

confidence: 99%

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

Zhang

et al. 2012

Oncology Letters

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Abstract. Human choriocarcinoma is one of the most aggressive malignant tumors characterized by early hematogenous spread to lung and brain tissues, and may be a cause of death in patients. Choriocarcinoma may occur following pregnancy and during implantation; however, trophoblastic invasion in human pregnancy is tightly regulated. The transforming growth factor-beta 1 (TGF-β1) has been suggested to play a role in controlling this process. In this study, we investigated the impact of TGF-β1 on invasion, as well as its sites of action in the TGF-β1/Smad pathway using a JEG-3 choriocarcinoma cell line. Following the treatment of cells with different doses of TGF-β1, cell invasion was observed. We also detected the expression of TGF-β receptor type I (TβR I) and TGF-β receptor type II (TβR II), Smad4, matrix metalloprotease (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in JEG-3 cells. Our data demonstrated that TGF-β1 promoted the invasive capability of JEG-3 cells depending on the downregulation of TβR I, TβR II, Smad4 and the upregulation of MMP-9 and TIMP-1. These observations suggest that TGF-β1 may play a critical role in the initiation of the trophoblastic invasion process. IntroductionA successful human pregnancy requires embryonic trophocytes to invade into the womb and adhere to the endometrium; however, this kind of invasion is strictly regulated temporospatially (1). The deregulation of the invasion process may cause a series of pregnancy-related diseases, such as hydatidiform mole and invasive mole; however, excessive invasion of trophocytes is significantly associated with the formation of placental choriocarcinoma (2). In this process, one critical step of choriocarcinoma invasion and metastasis is the degradation of the extracellular matrix (ECM), in which the MMP-9/TIMP-1 ratio plays a significant role (3,4).The main treatment for choriocarcinoma is 5-fluorouracil, which has a very good therapeutic efficacy; however, it may also cause toxic reactions, side effects and drug resistance (5). Since conventional treatments including surgery and chemotherapy often fail, it is necessary to explore the metastasis mechanisms of proliferation and invasiveness, and find a new target for drug therapy.TGF-β belongs to a growth factor super-family which consists of a highly evolutionary conserved group of secreted cytokines (6). The TGF-β family consists of TGF-β, activins, bone morphogenetic proteins (BMPs), nodals, inhibins and antimullerian hormone (AMH). TGF-β1 is the prototypic family member and is secreted as an inactive latent precursor (7,8). It plays a significant role in the control of growth and development, including the regulation of cell proliferation and differentiation, the promotion of ECM formation and suppression of the immune response (9). TGF-β1 exerts its cellular effects through TβR I, TβR II and the Smad transcription factors, which have pivotal roles in intracellular signaling (7,10). Moreover, Smad4 is an essential factor in TGF-β signaling and is a frequently mutated tumor ...

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Antimetastatic Role of Smad4 Signaling in Colorectal Cancer

Cited by 201 publications

References 21 publications

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

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