Abstract
BackgroundFunctional loss of the tumor suppressor Smad4 is involved in pancreatic and colorectal carcinogenesis and has been associated with the acquisition of invasiveness. We have previously demonstrated that the heterotrimeric basement membrane protein laminin-332 is a Smad4 target. Namely, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-332; its loss is thus implicated in the reduced or discontinuous deposition of the heterotrimeric basement membrane molecule as evident in carcinomas. Uncoupled expression of laminin genes, on the other hand, namely overexpression of the laminin-γ2 chain is an impressive marker at invasive edges of carcinomas where tumor cells are maximally exposed to signals from stromal cell types like macrophages. As Smad4 is characterized as an integrator of multiple extracellular stimuli in a strongly contextual manner, we asked if loss of Smad4 may also be involved in uncoupled expression of laminin genes in response to altered environmental stimuli. Here, we address Smad4 dependent effects of the prominent inflammatory cytokine TNFα on tumor cells.ResultsSmad4-reconstituted colon carcinoma cells like adenoma cells respond to TNFα with an increased expression of all three chains encoding laminin-332; coincubation with TGFβ and TNFα leads to synergistic induction and to the secretion of large amounts of the heterotrimer. In contrast, in Smad4-deficient cells TNFα can induce expression of the γ2 and β3 but not the α3 chain. Surprisingly, this uncoupled induction of laminin-332 chains in Smad4-negative cells rather than causing intracellular accumulation is followed by the release of γ2 into the medium, either in a monomeric form or in complexes with as yet unknown proteins. Soluble γ2 is associated with increased cell migration.ConclusionsLoss of Smad4 may lead to uncoupled induction of laminin-γ2 in response to TNFα and may therefore represent one of the mechanisms which underlie accumulation of laminin-γ2 at the invasive margin of a tumor. The finding, that γ2 is secreted from tumor cells in significant amounts and is associated with increased cell migration may pave the way for further investigation to better understand its functional relevance for tumor progression.
Highlights
Functional loss of the tumor suppressor Smad4 is involved in pancreatic and colorectal carcinogenesis and has been associated with the acquisition of invasiveness
Synergistic induction of laminin-332 in human adenoma cells in response to inflammatory cytokines TGFb and TNFa As an approach towards modelling the microenvironment in tumor tissues we here wished to address effects of TNFa, a prominent inflammatory cytokine produced by tumor infiltrating macrophages, on laminin-332 expression of Smad4-positive and Smad4-deficient tumor cells
The laminin-g2 chain, which is physiologically deposited in basement membranes as a component of the heterotrimeric laminin-332, is an impressive marker of invasive margins of aggressive carcinomas
Summary
Functional loss of the tumor suppressor Smad is involved in pancreatic and colorectal carcinogenesis and has been associated with the acquisition of invasiveness. The transition to malignancy is defined by breaking the basement membrane barrier In colorectal carcinomas, this is associated with a lack of laminin-511 and with irregular deposition of laminin-332 at invasive edges [9,10,11]. Relative overexpression of the laminin-g2 (and b3) chain has often been described and represents one of the most impressive molecular markers for the invasive front of colorectal and other cancer entities (for review see [12]). It marks socalled budding tumor cells [13,14]. Overexpression of g2 is believed to result from cellular responses to environmental signals illustrating that the regulation of laminin expression is subject to tumor cell intrinsic factors including the pattern of their respective genetic alterations and to extrinsic microenvironmental factors including signals from inflammatory cells in the tumor tissue
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