Loss of SMAD4 Alters BMP Signaling to Promote Colorectal Cancer Cell Metastasis via Activation of Rho and ROCK

Abstract

Loss of SMAD4 from colorectal cancer cells causes BMP signaling to switch from tumor suppressive to metastasis promoting. Concurrent loss of SMAD4 and normal expression of BMP receptors in colorectal tumors was associated with reduced survival times of patients. Reagents that interfere with SMAD4-independent BMP signaling, such as ROCK inhibitors, might be developed as therapeutics for CRC.

Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer

“…Smad4 and p53 are reported to be key molecules affecting the functional roles of BMPs in colorectal cancer progression. Voorneveld and colleagues reported that loss of Smad4 switches BMPs from antitumorigenic to protumorigenic, whereas p53 mutations suppress the enhancement of chemosensitivity by BMP signaling in colorectal cancer cells with wild-type Smad4 (24,25). Because p53 was mutated in all colorectal cancer cells used in the current study (26), the association between p53 status and the protumorigenic role of BMP signaling in colorectal cancer could not be assessed in our study.…”

Epithelial–mesenchymal transition in colorectal cancer metastasis: A system review

“…Most interestingly, Smad4 is also a central component of bone morphogenetic protein (BMP) signaling pathway. The loss of Smad4 causes BMP signaling to switch from tumor suppressive to metastasis promoting by triggering EMT and activation of Rho and ROCK [73]. Taken together, these findings suggest that loss of Smad4 may underlie the functional shift of TGF-␤ and BMP from a tumor suppressor to a tumor promoter.…”

Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis

“…The SMAD4-independent TGFb pathway coupled with loss of SMAD4 was reported to be involved in the tumor-promoting effects of TGFb, such as epithelial-to-mesenchymal transition, migration, invasion, tumorigenicity, and metastasis (19,20). In addition, it was recently reported that loss of SMAD4 activates SMAD4-independent BMP signaling to promote colorectal cancer metastasis via activation of Rho and ROCK (21). In addition to the cell-autonomous changes in cancer cells, the cross-talk between cancer cells and stromal cells plays key roles in malignant progression.…”