Abstract
During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
Highlights
During mammalian embryonic development, primary cilia with microtubule-based cellular organelles protrude from the surface of the cell [1]
One hypothesis has been proposed that states that the behavior of mesenchymal and endothelial cells is affected by Sonic hedgehog (SHH), which is secreted from pancreatic cancer in a paracrine manner [78,79]
Li et al emphasized that the activity of the SHH pathway is low in normal pancreatic tissue, whereas in pancreatic adenocarcinoma, the activity of the SHH pathway signaling in tumor epithelia and surrounding stromal tissue becomes higher [79]
Summary
Primary cilia with microtubule-based cellular organelles protrude from the surface of the cell [1]. Primary cilia transduce and regulate several signaling pathways such as Sonic hedgehog (SHH) and Wingless-activated (WNT) [1]. CAFs fuel cancer cells via secreting soluble factors to trigger metastasis and chemoresistance These triggers include extracellular acidification, inflammation, activation of matrix metalloproteases, and decreased efficacy of chemotherapeutic drugs [7,8,9,10,11,12]. SMO can activate GLI to regulate target gene expression and affect migration/invasion, cell cycle, tumor growth, and cancer stem cells. HH ligands secreted by tumor cells activate the signaling in the surrounding stroma, which provides a favorable microenvironment for tumor growth. The pathway involves the development of neural tube, lung, skin, axial skeleton, gastrointestinal tract, pancreas, and other organs, as well as the regulation of tissue homeostasis and stem cell behavior [19]. Though SHH is important in embryonic vessel formation, its role in tumor vasculature remains unclear
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