Sonic Hedgehog Signaling Pathway Supports Cancer Cell Growth during Cancer Radiotherapy

Abstract

Tumor growth after radiotherapy is a commonly recognized cause of therapeutic failure. In this way, we examined tumor cell growth after radiotherapy by establishing a cancer cell growth model in vitro. We accomplished this model by seeding non-irradiated firefly luciferase2 and green fluorescent protein fusion gene (Fluc) labeled living cancer reporter cells onto a feeder layer of irradiated cancer cells. The living tumor cell growth was monitored by bioluminescence imaging. The living reporter cells grew faster when seeded onto lethally irradiated feeder cells than when seeded onto non-irradiated feeder cells or when seeded in the absence of feeder cells. We found that the expression levels of the Shh and Gli1 proteins, both of which are critical proteins in Sonic hedgehog (SHH) signaling, were increased after irradiation and that this expression was positively correlated with reporter cell growth. Moreover, the dying cell stimulation of living tumor cell growth was enhanced by the addition of SHH signaling agonists and inhibited by SHH signaling antagonists. SHH agonists also enhanced reporter cell growth in the absence of irradiated feeder cells, suggesting this mechanism plays a role in feeder cell growth stimulation. Given these results, we conclude that SHH signaling activation plays an important role during tumor repopulation after radiotherapy.

Hedgehog Signaling Drives Radioresistance and Stroma-Driven Tumor Repopulation in Head and Neck Squamous Cancers

“…The implications of our findings are important since tumors with up-regulated Gli1 and/or the EMT pathway have been shown to be more chemo- and radioresistant, more locally invasive, and metastatic (7, 21–23). Secondly, the peripheral tumor cells model those cell islands left behind after surgical resection (“positive margin”).…”

“…Therefore, we decided to evaluate whether HhP inhibition could enhance tumor control by either increasing radiosensitivity or preventing tumor repopulation in vivo . A recent paper indicated that inadequate RT doses in other tumor cell lines can lead to increased tumor regrowth mediated by the HhP (21). Therefore, direct inhibition of Gli1 activation in vivo may lead to enhanced tumoricidal effects when combined with RT.…”

Dying tumor cells stimulate proliferation of living tumor cells via caspase‐dependent protein kinase Cδ activation in pancreatic ductal adenocarcinoma

“…In breast cancer cells, PGE 2 was thought to increase the growth of living tumor cells, but we wish to explore additional signaling pathway in pancreatic cancer in this study. Interestingly, we recently showed that dying cells stimulate living tumor cell growth through the activation of the Sonic Hedgehog (SHH) signaling pathway and this effect was observed in pancreatic tumor cells (Ma et al., 2013). It is generally considered that apoptosis is one of the main cell death mechanisms following exposure to irradiation and execution of apoptosis is closely linked to serial activation of a family of proteases called caspases via external or internal inducers; and irrespective of the actual route to caspase activation, both pathways will lead to the activation of the effector caspases, caspase 3, caspase 6 and caspase 7 which perform much of the proteolysis.…”

Cyclopamine-Loaded Core-Cross-Linked Polymeric Micelles Enhance Radiation Response in Pancreatic Cancer and Pancreatic Stellate Cells

“…In some cases, IR-induced tumor shrinkage was followed by tumor regrowth 18 . Recent studies found that SHH activation could protect tumor cells against IR 19 ; while co-treatment with CPA, a potent SHH inhibitor, could enhance tumor response to IR 19b, 20 . CPA-induced radio-sensitization was attributed to factors including cell cycle arrest, depletion of cancer stem cells and disruption of DNA damage repair 21 .…”