Lessons learned from SMAD4 loss in squamous cell carcinomas

Abstract

SMAD4 is a potent tumor suppressor and the primary mediator of the TGFß signaling pathway. SMAD4 genetic loss is frequent in squamous cell carcinomas (SCCs). Reports of SMAD4 expression in SCCs vary significantly possibly due to inter-tumor heterogeneity or technical reasons. SMAD4 loss is an initiation event for SCCs. In tumor epithelial cells, SMAD4 mutant SCCs commonly present with increased proliferation, decreased apoptosis, and “Brca-like” genomic instability associated with DNA repair defects. SMAD4 loss also plays a role in expansion of cancer stem cells (CSC). Epithelial SMAD4 loss causes overexpression of TGFß which is released into the tumor microenvironment and contributes to SCC progression through pro-inflammatory and immune evasive mechanisms. SMAD4 loss, while not directly targetable, is associated with multiple targetable pathways that require further studies. Altogether, SMAD4 loss is a potential biomarker in SCCs that should be further studied to gain insight for prognosis and therapeutic approaches to potentially guide future clinical trials and improve SCC patient outcomes.

Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy

“…The term “Smad” was a combination of the sma gene of Caenorhabditis elegans and the mad gene of Drosophila melanogaster [ 31 ]. Subsequently, Smad4 mutations were found in additional types of tumors, such as gastrointestinal carcinoid[ 32 ], prostate cancer[ 33 ], squamous cell carcinoma[ 34 ], and lung cancer[ 35 ]. The gene coding for Smad4 is located at human chromosome locus 18q21.1 (Figure 1A ) and is composed of 12 exons and 10 introns[ 36 ].…”

Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies?

“…Indeed, in different tumor types, inactivation of SMAD4 has been described to promote tumor progression by a number of mechanisms. Among them are inactivation of tumor suppressor genes APC, VEGF overexpression, increase of MMP-9 activity and of GLUT1 levels, as well as recruitment of CCR1+ myeloid cells in colorectal cancer [148,149], activation of K-Ras mutations in pancreatic duct adenocarcinoma [150,151], inhibition of DNA repair mechanisms and finally, increased levels of genomic instability in lung and skin cancer [152,153].…”

The role of Smad4 in the regulation of insulin resistance, inflammation and cell proliferation in HTR8‐Svneo cells

“…The Smad4 works as a general partner of the receptor‐regulated SMADs (R‐SMADs) to form a complex for the translocation from cytoplasm to nucleus, which ultimately regulates the transcription of TGF‐β response genes 8 . It has been demonstrated that the SMAD family makes large contributions to various physiological process, including the cell differentiation, proliferation, early growth, apoptosis, homeostasis and even tumour development, while Smad4 is universally regarded as a key tumour suppressor 10 . Especially, the protective role of Smad4 in tumour proliferation is initially identified in pancreatic cancers, 11 and the high prevalence in genetic loss of Smad4 is also found in squamous cell carcinomas (SCCs) 10,12 .…”

“…It has been demonstrated that the SMAD family makes large contributions to various physiological process, including the cell differentiation, proliferation, early growth, apoptosis, homeostasis and even tumour development, while Smad4 is universally regarded as a key tumour suppressor 10 . Especially, the protective role of Smad4 in tumour proliferation is initially identified in pancreatic cancers, 11 and the high prevalence in genetic loss of Smad4 is also found in squamous cell carcinomas (SCCs) 10,12 . Besides, the crosstalk between metabolic abnormalities and SMAD signalling has also been revealed in several studies.…”