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Smad7 induces hepatic metastasis in colorectal cancer.

Halder SK, Rachakonda G, Deane NG, Datta PK - Br. J. Cancer (2008)

Bottom Line: Increased expression of TGF-beta type II receptor in liver metastases is associated with phosphorylation and nuclear accumulation of Smad2.Immunohistochemical analyses have suggested poorly differentiated spindle cell morphology and higher cell proliferation in Smad7-induced liver metastases.Interestingly, we have observed increased expression and junctional staining of Claudin-1, Claudin-4 and E-cadherin in liver metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

ABSTRACT
Although Smad signalling is known to play a tumour suppressor role, it has been shown to play a prometastatic function also in breast cancer and melanoma metastasis to bone. In contrast, mutation or reduced level of Smad4 in colorectal cancer is directly correlated to poor survival and increased metastasis. However, the functional role of Smad signalling in metastasis of colorectal cancer has not been elucidated. We previously reported that overexpression of Smad7 in colon adenocarcinoma (FET) cells induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. Here, we have observed that abrogation of Smad signalling by Smad7 induces liver metastasis in a splenic injection model. Polymerase chain reaction with genomic DNA from liver metastases indicates that cells expressing Smad7 migrated to the liver. Increased expression of TGF-beta type II receptor in liver metastases is associated with phosphorylation and nuclear accumulation of Smad2. Immunohistochemical analyses have suggested poorly differentiated spindle cell morphology and higher cell proliferation in Smad7-induced liver metastases. Interestingly, we have observed increased expression and junctional staining of Claudin-1, Claudin-4 and E-cadherin in liver metastases. Therefore, this report demonstrates, for the first time, that blockade of TGF-beta/Smad pathway in colon cancer cells induces metastasis, thus supporting an important role of Smad signalling in inhibiting colon cancer metastasis.

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A model showing the role of Smad7 signalling in colon cancer metastasis. The TGF-β activates TβR heterotetrameric complex, leading to activation of the classical Smad2, Smad3 and Smad4 signalling cascade that induces cyclin-dependent kinase inhibitor p21Cip1 and suppresses pro-oncogenic c-Myc expression. The p21Cip1 expression leads to inhibition of cyclin-dependent kinases (CDKs) and cyclins that results in hypophosphorylation of Rb, repression of E2F transcriptional activity and inhibition of cell cycle progression. Smad7 negatively regulates TGF-β/Smad signalling pathways to induce cell proliferation by suppressing p21Cip1 and by induction of c-Myc. Smad7 induces cell survival through the activation of AKT and inhibits apoptosis through the induction of TRX (thioredoxin-1) and ASK1 (apoptosis signal-regulating kinase-1). Smad7 also cooperates with activated Ras and induces tumorigenicity. All of these deregulations of cell behaviour may finally contribute to metastasis. Smad7 expression is induced by TGF-β, EGF, TNF-α and IFN-γ.
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fig5: A model showing the role of Smad7 signalling in colon cancer metastasis. The TGF-β activates TβR heterotetrameric complex, leading to activation of the classical Smad2, Smad3 and Smad4 signalling cascade that induces cyclin-dependent kinase inhibitor p21Cip1 and suppresses pro-oncogenic c-Myc expression. The p21Cip1 expression leads to inhibition of cyclin-dependent kinases (CDKs) and cyclins that results in hypophosphorylation of Rb, repression of E2F transcriptional activity and inhibition of cell cycle progression. Smad7 negatively regulates TGF-β/Smad signalling pathways to induce cell proliferation by suppressing p21Cip1 and by induction of c-Myc. Smad7 induces cell survival through the activation of AKT and inhibits apoptosis through the induction of TRX (thioredoxin-1) and ASK1 (apoptosis signal-regulating kinase-1). Smad7 also cooperates with activated Ras and induces tumorigenicity. All of these deregulations of cell behaviour may finally contribute to metastasis. Smad7 expression is induced by TGF-β, EGF, TNF-α and IFN-γ.

Mentions: Recent studies have demonstrated that Smad7 expression is induced by TGF-β, EGF and the inflammatory cytokines, such as TNF-α and IFN-γ (Afrakhte et al, 1998; Takahara et al, 2005). Upregulation of Smad7 may induce cell proliferation through the inhibition of p21Cip1 (Harper et al, 1995; Robson et al, 1999) and suppress TGF-β-mediated growth inhibition through the induction of c-Myc (Yagi et al, 2002). The higher levels of Smad7 can induce cell survival (Edlund et al, 2005) and inhibit apoptosis (Arnold et al, 2004). Smad7 has been shown to induce tumorigenicity in cooperation with activated Ras (Liu et al, 2003). Thus, increased cell proliferation, survival and tumorigenicity, as well as the inhibition of apoptosis, may contribute to Smad7-induced metastatic growth in the lever (Figure 5). In conclusion, we have established a mouse model for splenic injection of colon adenocarcinoma FET cells that develop liver metastasis when Smad7 is overexpressed. Smad7 not only blocks TGF-β-mediated antitumour function, but also promotes tumour progression and metastasis of colorectal cancer probably through the cooperation with oncogenic Ras. Although Smad pathway has been shown to mediate the prometastatic function of TGF-β in the development of metastases of breast cancer (Kang et al, 2005) and melanoma (Javelaud et al, 2007) in mouse model, our results provide the first evidence that blockade of Smad pathway by Smad7 in colon cancer cells increases liver metastasis. Thus, Smad7 could be a potential target for therapeutic intervention of colorectal cancers.


Smad7 induces hepatic metastasis in colorectal cancer.

Halder SK, Rachakonda G, Deane NG, Datta PK - Br. J. Cancer (2008)

A model showing the role of Smad7 signalling in colon cancer metastasis. The TGF-β activates TβR heterotetrameric complex, leading to activation of the classical Smad2, Smad3 and Smad4 signalling cascade that induces cyclin-dependent kinase inhibitor p21Cip1 and suppresses pro-oncogenic c-Myc expression. The p21Cip1 expression leads to inhibition of cyclin-dependent kinases (CDKs) and cyclins that results in hypophosphorylation of Rb, repression of E2F transcriptional activity and inhibition of cell cycle progression. Smad7 negatively regulates TGF-β/Smad signalling pathways to induce cell proliferation by suppressing p21Cip1 and by induction of c-Myc. Smad7 induces cell survival through the activation of AKT and inhibits apoptosis through the induction of TRX (thioredoxin-1) and ASK1 (apoptosis signal-regulating kinase-1). Smad7 also cooperates with activated Ras and induces tumorigenicity. All of these deregulations of cell behaviour may finally contribute to metastasis. Smad7 expression is induced by TGF-β, EGF, TNF-α and IFN-γ.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2538763&req=5

fig5: A model showing the role of Smad7 signalling in colon cancer metastasis. The TGF-β activates TβR heterotetrameric complex, leading to activation of the classical Smad2, Smad3 and Smad4 signalling cascade that induces cyclin-dependent kinase inhibitor p21Cip1 and suppresses pro-oncogenic c-Myc expression. The p21Cip1 expression leads to inhibition of cyclin-dependent kinases (CDKs) and cyclins that results in hypophosphorylation of Rb, repression of E2F transcriptional activity and inhibition of cell cycle progression. Smad7 negatively regulates TGF-β/Smad signalling pathways to induce cell proliferation by suppressing p21Cip1 and by induction of c-Myc. Smad7 induces cell survival through the activation of AKT and inhibits apoptosis through the induction of TRX (thioredoxin-1) and ASK1 (apoptosis signal-regulating kinase-1). Smad7 also cooperates with activated Ras and induces tumorigenicity. All of these deregulations of cell behaviour may finally contribute to metastasis. Smad7 expression is induced by TGF-β, EGF, TNF-α and IFN-γ.
Mentions: Recent studies have demonstrated that Smad7 expression is induced by TGF-β, EGF and the inflammatory cytokines, such as TNF-α and IFN-γ (Afrakhte et al, 1998; Takahara et al, 2005). Upregulation of Smad7 may induce cell proliferation through the inhibition of p21Cip1 (Harper et al, 1995; Robson et al, 1999) and suppress TGF-β-mediated growth inhibition through the induction of c-Myc (Yagi et al, 2002). The higher levels of Smad7 can induce cell survival (Edlund et al, 2005) and inhibit apoptosis (Arnold et al, 2004). Smad7 has been shown to induce tumorigenicity in cooperation with activated Ras (Liu et al, 2003). Thus, increased cell proliferation, survival and tumorigenicity, as well as the inhibition of apoptosis, may contribute to Smad7-induced metastatic growth in the lever (Figure 5). In conclusion, we have established a mouse model for splenic injection of colon adenocarcinoma FET cells that develop liver metastasis when Smad7 is overexpressed. Smad7 not only blocks TGF-β-mediated antitumour function, but also promotes tumour progression and metastasis of colorectal cancer probably through the cooperation with oncogenic Ras. Although Smad pathway has been shown to mediate the prometastatic function of TGF-β in the development of metastases of breast cancer (Kang et al, 2005) and melanoma (Javelaud et al, 2007) in mouse model, our results provide the first evidence that blockade of Smad pathway by Smad7 in colon cancer cells increases liver metastasis. Thus, Smad7 could be a potential target for therapeutic intervention of colorectal cancers.

Bottom Line: Increased expression of TGF-beta type II receptor in liver metastases is associated with phosphorylation and nuclear accumulation of Smad2.Immunohistochemical analyses have suggested poorly differentiated spindle cell morphology and higher cell proliferation in Smad7-induced liver metastases.Interestingly, we have observed increased expression and junctional staining of Claudin-1, Claudin-4 and E-cadherin in liver metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

ABSTRACT
Although Smad signalling is known to play a tumour suppressor role, it has been shown to play a prometastatic function also in breast cancer and melanoma metastasis to bone. In contrast, mutation or reduced level of Smad4 in colorectal cancer is directly correlated to poor survival and increased metastasis. However, the functional role of Smad signalling in metastasis of colorectal cancer has not been elucidated. We previously reported that overexpression of Smad7 in colon adenocarcinoma (FET) cells induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. Here, we have observed that abrogation of Smad signalling by Smad7 induces liver metastasis in a splenic injection model. Polymerase chain reaction with genomic DNA from liver metastases indicates that cells expressing Smad7 migrated to the liver. Increased expression of TGF-beta type II receptor in liver metastases is associated with phosphorylation and nuclear accumulation of Smad2. Immunohistochemical analyses have suggested poorly differentiated spindle cell morphology and higher cell proliferation in Smad7-induced liver metastases. Interestingly, we have observed increased expression and junctional staining of Claudin-1, Claudin-4 and E-cadherin in liver metastases. Therefore, this report demonstrates, for the first time, that blockade of TGF-beta/Smad pathway in colon cancer cells induces metastasis, thus supporting an important role of Smad signalling in inhibiting colon cancer metastasis.

Show MeSH
Related in: MedlinePlus