The Role of Sonic Hedgehog Reemergence During Gastric Cancer

Abstract

Sonic Hedgehog (Shh) signaling has been extensively studied for its role in developmental biology and cancer biology. The association between Shh and cancer development in general is well established but the functional role of Shh in the development and progression of gastric cancer specifically is largely unknown. Bone marrow-derived stem cells, specifically mesenchymal stem cells (MSCs) infiltrate and engraft into the gastric mucosa in response to the chronic inflammatory environment of Helicobacter infection. In this review, MSC infiltration and changes in the cytokine and cellular profiles of later-stage chronic environments will be tied into their interactions with the Shh pathway. We will discuss how these changes shape tumorigenesis and tumor progression in the gastric mucosa. The current review focuses on the Shh signaling pathway and its role in the development of gastric cancer, specifically in response to Helicobacter pylori infection. We follow with an in-depth discussion of the regulation of the Hedgehog pathway during acute and chronic gastric inflammation with a focus on signaling within the MSC compartment.

HSulf-1 suppresses cell growth and down-regulates Hedgehog signaling in human gastric cancer cells

“…Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), penicillin (100 IU/ml) and streptomycin (100 µg/ml) in a humidified incubator at 37˚C with a 5% CO 2 atmosphere. Cells (1x10 4 ) were plated in 12-well plates one day prior to transfection. Monoclonal cells stably expressing HSulf-1 or empty vector were established following plasmid transfection and Geneticin (G418 sulfate) selection.…”

“…Emerging evidence revealed that gastric cancer results from a combination of factors, including Helicobacter pylori-induced inflammation and deregulation of the Wnt and Hedgehog signaling pathways (2)(3)(4). The Hedgehog (Hh) family of proteins controls multiple cellular functions, including cell growth, survival and outcome, as well as body patterning and organ morphogenesis (5).…”

Gastric cancer stem cells: therapeutic targets

“…High levels of Shh found in GC may be caused by repopulation of the gastric mucosa by SCs, which possibly includes the recruitment of bone marrow-derived mesenchymal stem cells (BM-MSCs) as a part of the inflammatory response [24,88]. BM-MSCs were found to possess the property of spontaneous transformation [93], whereas the Hh pathway was recognized as the key factor for growth and proliferation of these spontaneously transformed MSCs in vivo [94]. MSC-like cells have been isolated from both human GC and adjacent noncancerous tissue [95].…”

Oncogenic Signaling in Gastric Carcinoma

“…The binding of Shh to Ptch results in loss of Ptc activity and consequently Smo activation. Smo activation triggers Hh signal into the cytoplasm by triggering activation of Glioblastoma family transcription factors (Gli1, Gli2 and Gli3) that induce transcription of signaling targets like Wnt and the zinc finger transcription factor, Snail (Martin et al, 2010). Gli 1 induces the transcription of Snail that inhibits E-cadherin transcription.…”