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Review
. 2019 Sep;58(9):1648-1655.
doi: 10.1002/mc.23049. Epub 2019 May 29.

Lessons learned from SMAD4 loss in squamous cell carcinomas

Ariel L Hernandez  1 , Christian D Young  1 , Jing H Wang  2   3 , Xiao-Jing Wang  1   4
Affiliations
Review

Lessons learned from SMAD4 loss in squamous cell carcinomas

Ariel L Hernandez et al. Mol Carcinog. 2019 Sep.

Abstract

SMAD4 is a potent tumor suppressor and a central 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 loss causes increased proliferation, decreased apoptosis, and "Brca-like" genomic instability associated with DNA repair defects. SMAD4 loss also plays a role in the expansion of cancer stem cells. Epithelial SMAD4 loss causes overexpression of TGFß that is released into the tumor microenvironment and contributes to SCC progression through proinflammatory and immune evasive mechanisms. SMAD4 loss, while not a direct therapeutic target, is associated with multiple targetable pathways that require further therapeutic studies. Altogether, SMAD4 loss is a potential biomarker in SCCs that should be further studied for its values in prognostic and therapeutic predictions. Such information will potentially guide future biomarker-driven clinical trial designs and improve SCC patient outcomes.

Keywords: SCCs; SMAD4 loss; prevalence; tumor initiation; tumor progression.

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Figures

Figure 1.
Figure 1.. Normal versus deficient SMAD4 signaling.
(a) SMAD4 dependent TGFβ signaling in normal epithelial and stromal cells. (b) SMAD4 loss results in increased TGFβ production and release TGFβ into the extracellular matrix that acts on stromal cells, inducing a pro-tumorigenic microenvironment.
Figure 2.
Figure 2.. “Brca-like” phenotype in SMAD4 deficient keratinocytes.
(a) DNA repair and replication in normal, DNA damaged, and Fanconi anemia cells. (b) Karyotype of SMAD4 null keratinocytes treated with mitomycin C (40 ng/mL) leads to chromatin with radial structures (red circles) and chromosome breaks (red arrows), hallmarks observed in Fanconi anemia patients.
Figure 3.
Figure 3.. SMAD4 deficient SCC initiation and progression.
Loss of SMAD4 causes increased genomic instability to initiate SCC formation and progression. A pro-tumorigenic microenvironment is induced by TGFβ-associated inflammation and immune suppression to promote tumor growth and metastatic progression.
See this image and copyright information in PMC

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