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Review Article
Journal of Chinese Integrative Medicine: Volume 10, 2012   Issue 3
Advances in Smoothened-targeting therapies for pancreatic cancer: implication for drug discovery from herbal medicines
1. Jin-bin Han (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China )
2. Yong-qiang Hua (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China )
3. Lian-yu Chen (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China )
4. Lu-ming Liu (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China E-mail: llm1010@163.com)
ABSTRACT: Smoothened (SMO) is a member of sonic hedgehog homology (SHH) signaling pathway. It plays a key role as a bridge between patched-1 (PTCH-1) and Gli. Aberrant SHH expression can be detected in various malignant tissues, and the expression in pancreatic cancer stem cells is higher apparently. SHH signals are closely associated with self-duplication of cancer stem cells, formation of tumor vessels as well as matrixes. SMO antagonists such as cyclopamine, GDC-0449 and so on show potential to inhibit activity of SHH signaling, and arrest the growth as well as metastases of tumors. Recently, a few of SMO antagonists have been studied in phase Ⅰ clinical trials and some are in phase Ⅱ, meanwhile, phase Ⅰ or Ⅱ trials of SMO antagonists to treat pancreatic cancer are performed currently. As the classical SMO antagonist, cyclopamine is extracted from a medicinal plant. Perhaps researchers may be able to determine more effective SMO-targeting drugs from herbal medicines in the future.

Received August 28, 2011; accepted November 21, 2011; published online March 15, 2012.
Full-text LinkOut at PubMed. Journal title in PubMed: Zhong Xi Yi Jie He Xue Bao.

基金项目:国家自然科学基金面上项目资助项目(No. 81072942); 国家自然科学基金青年科学基金资助项目 (No. 30901911)
Correspondence: Lu-ming Liu, MD, Professor; Tel: 021-64175590-3638; E-mail: llm1010@163.com


     The sonic hedgehog homolog (SHH) signaling pathway plays a key role in the behaviors of cancer stem cells, including proliferation, self-replication, differentiation, and the development of the cancerous microenvironment[1]. As a component of the SHH signaling pathway, the Smoothened (SMO) protein acts as a bridge across the upper and lower transduction processes. The number of stem cells in a group of cancer cells can be decreased by inhibiting SHH signaling with SMO antagonists, thereby increasing the effects of chemotherapy and the biological response to cytotoxic drugs. Recent advances in the field of SMO-targeting therapy, as they relate to the treatment of pancreatic cancer, are reviewed in this article.


1  SMO and the hedgehog pathway
Hedgehog (HH) is an important signaling pathway that regulates both the short- and long-term development of several organs. In mammals, there are three homologous HH genes — SHH, Indian hedgehog (IHH), and desert hedgehog (DHH) — that encode the proteins SHH, IHH, and DHH, respectively. In cells that express HH, the generated HH proteins are involved in secretory pathways and lipid modification. They are responsible for adding 16-acyl to NH2 and cholesterol to carboxyl terminals. The subsequent release of HH depends on the transmembrane protein, dispatched, and the diffusion of HH depends on the tout velu-dependent synthesis of heparin sulfate proteoglycans[2]. If no HH signal is received by the cells that require stimulation, the 12-transmembrane receptor patched-1 (PTCH-1) blocks the 7-transmembrane protein SMO, which is located on the surface of the cell, thereby leading to the loss of activity[3]. When the HH ligand binds to PTCH-1, SMO is released and the HH pathway is activated. HH conjugates proteins, including the HH interaction protein, and growth arrest-specific gene-1 (Gas-1) closely regulates the number of PTCH-1 receptors that bind to HH. However, newly discovered single transmembrane proteins, such as cell adhesion molecule-related/down-regulated by oncogenes (Cdon/Cdo) and brother of Cdo (Boc), promote binding between the HH ligand and PTCH-1[4].
     The result of HH signaling varies depending on the type of receptor cells. Generally, genes that are induced by HH activity, such as PTCH-1, Hip1, and Gli1, can trigger positive or negative feedback of the pathway, thereby modifying the strength or duration of the HH signal. Additional HH targets include genes that regulate proliferation, differentiation (e.g., CyclinD1, CyclinD2, N-Myc, Wnts, PdgfRa, Igf2, FoxM1, and Hes1), survival (Bcl-2), self-renewal, epithelial-mesenchymal transition during angiogenesis, and invasiveness[5]. In general, it is believed that SMO anchors to the cell surface, thereby initiating the signaling cascade and activating Gli family members, such as zinc-finger transcription factors[6]. Vertebrates have three kinds of Gli proteins — Gli1, Gli2 and Gli3. Gli1 and Gli2 activate HH-targeted genes, while Gli3 mainly inhibits the HH signal. If there is no HH signal, Gli is phosphorylated by several kinds of protein kinases, such as protein kinase A, glycogen synthase 3H and casein kinase 1A, resulting in the cleavage of Gli-mediated proteasomes and the formation of NH2-terminal proteins that are inhibitors of HH-targeted genes[7]. As an inhibitor, suppressor of fused (SUFU) binds to Gli in the cytoplasm and nuclei, thereby inhibiting HH signals and repressing Gli in order to activate its target genes[8].
     PTCH-1 mutations may induce basal cell carcinoma syndrome (also known as Gorlin syndrome), medulloblastomas, precancerosis, and rhabdomyosarcoma[9]. Inactivation of PTCH-1 or excessive expression of HH-targeted genes have been detected in most basal cell carcinomas, and deregulation of the HH pathway may play a vital role in the development of cancer[10]. Mutations to PTCH-1, SMO and SUFU and enhancement of the HH signal have been observed in medulloblastoma cells[11]. Furthermore, excessive expression of HH in its targeted genes has been detected in multiple kinds of cancerous cells such as pulmonary, gastric, pancreatic, and prostate cancer cells[12]. In the tissues of flies, the combination of HH and PTCH-1 leads to SMO anchoring to the surface of a complex related to the fused serine/threonine protein (Fu) kinase and kinesin Cos-2[13], and, subsequently, Fu and Cos-2 transporting signals from SMO to cubitus interruptus proteins. Due to the lack of homologous Cos-2 genes in vertebrates, HH signal transduction does not need the direct participation of Fu (perhaps because there is no mechanism like this in vertebrates)[14]. It is the hot spot of HH studies that how signals are transducted from SMO to Gli.


2  SMO and the pathogenesis of pancreatic cancer

2.1  Genesis of pancreatic cancer  The deregulation of SHH is believed to be an important factor that promotes and maintains pancreatic cancer[15]. SHH is a morphogen involved in embryonic development, and its exact regulation mechanism is crucially important to the development of normal pancreatic tissue. Excessive expression of SHH injures the morphology of the pancreas, increasing the mesenchyme and decreasing the cortex[16]. SHH activity has never been detected in normal adult pancreatic tissue, but the aberrant expression of SHH in the mesoderm of the pancreas may lead to the malformation of the pancreatic mesoderm and the generation of excessive interstitial cells[17]. Aberrant expression of SHH has not only been noted in pancreatic cancers, but also some precancerous lesions such as pancreatic epithelioblastomas and ductal papillary-mucinous tumors. Therefore, the deregulation of SHH may take place in the early stages of cancer development.
     Jones et al[18] reported that 67% to 100% of pancreatic cancer tissues demonstrate the deregulation of SHH and the aberrant state of 19 other related genes. In addition, several mutated genes have been noted in pancreatic cancer tissue, including SOX3, LRP2, TBX5, Gli1, Gli3, BOC, BMPR2 or CREBBP. A report of Johns Hopkins University demonstrated that the abnormal activation of SHH is always present in the Pdx-1-Cre, LsL-Kras (12D), and Ink4a/Arf (Iox/Iox) transgenic rats that serve as pancreatic cancer models[19]. Among the various molecules that take part in the SHH pathway, SMO is one of the key transport signals that translates Gli2 to a transcriptional activator, thereby inducing the activation of SHH-targeted genes[20]. The growth of pancreatic cancer can be blocked via the inhibition of SHH activity, and it is believed that the autocrine passage is also inhibited, resulting in the proliferation, maintenance, and metastasis of cancer cells[21].
2.2  SMO participates in the microenvironment and the angiogenesis of pancreatic cancers  A study that utilized a rat model demonstrated that the depletion of SMO in pancreatic epithelia did not attenuate the formation of tumors and that the SHH ligand did not cause SHH activation in pancreatic cancer cells. Meanwhile, the transgenic expression of the allelomorphic SMO gene in pancreatic epithelia did not cause any changes in SMO-targeted genes or tumors[22]. Based on these findings, the conclusion was drawn that the SHH signal participates in paracrine secretion and the formation of the cancerous microenvironment in epithelial cancer cells without SHH signaling activity. New vessels are developed via precursor interactions, and transmission is stimulated by the SHH ligand. Furthermore, SHH activates the matrix fibroblasts, resulting in a stable vascular system[23,24]. Within the microenvironment of cancers, bone marrow plasma cells (BMPCs) may differentiate into multiple types of cells, and the antineoplastic activity of the SHH inhibitor may be mediated by multiple chemicals within the matrix of the tumor. Furthermore, the fibroblasts in the connective tissues of pancreatic cancers show important responses to SHH signaling. Based on previous studies on rat models, fibroblasts play a critical role in the growth of tumors because embryonic fibroblasts promote the growth of pancreatic cancers[25]. Bailey et al[26] reported that Gli1 and SHH may promote the proliferation of pancreatic astrocytes, inducing them to differentiate into the blast cells of muscle fibers, thereby resulting in the formation of pancreatic cancer fibroblasts.
2.3  SMO regulates pancreatic cancer stem cells  A subgroup of pancreatic cancer cells that expresses CD44, CD24, and epithelial-specific antigen (ESA) account for 0.2% to 0.8% of cells with 100-fold higher tumorigenesis than the general population of cells. CD44+, CD24+ and ESA+ pancreatic cancer cells can self-duplicate and differentiate, acting as stem cells. Most researchers define these types of cells as pancreatic cancer stem cells[1].
     The SHH signaling pathway maintains tissue stabilization by regulating the self-duplication of normal stem cells and the proliferation and differentiation of progenitor cells. In glioma tissues, CD133+ cancer stem cells express SHH, Gli1 and PTCH-1. Furthermore, the mechanisms of stem cell self-duplication, development, and generation require the participation of SMO and Gli1[27]. CD44+ and CD24/low/Lin 2 breast cancer stem cells highly express Gli1 and PTCH-1[28], and the high expression of SHH has been demonstrated in multiple myeloma stem cells[29]. Moreover, colon cancer stem cells require the SHH signaling pathway to maintain their development. In the multiple myeloma cells that express the SHH signal, clusters of cancer stem cells can be detected and SHH ligands promote the multiplication of stem cells, but not differentiation. Clonal multiplication related to the terminal differentiation of multiple myeloma stem cells can be suppressed by inhibiting the SHH signaling pathway[5]. The high expression of aldehyde dehydrogenase (ALDH) is an important characteristic of leukemia stem cells, while the SHH inhibitor, cyclopamine, has the ability to decrease the expression level to three-fold lower than the original expression level. In other words, SHH signals are critical to the development of leukemia stem cells. Both the self-duplication of pancreatic cancer stem cells and the tumorigenesis of pancreatic cancer require the participation of SHH signaling. Li et al[30] reported that the expression of SHH mRNA in CD44+, CD24+ and ESA+ pancreatic cancer stem cells was 46 times higher than normal pancreatic cells and four times higher than CD44, CD24 and ESA pancreatic cancer cells or pancreatic cancer tissues. Although there are no reports on the regulation of SHH signaling in pancreatic cancer stem cells, the conclusion can be reached that SHH plays a critical role in the self-duplication and differentiation of pancreatic cancer stem cells. However, other study results indicate the high expression of SHH in pancreatic cancer stem cells and other types of cancer cells [31].


3  SMO antagonists
Cyclopamine is a steroidal alkaloid extracted from Veratrum Californicum and can inhibit SHH signaling by directly binding with SMO. The binding location of SMO and cyclopamine is the 7-helix bundle of the SMO protein. Moreover, this combination impacts the conformation of SMO. The combination of cyclopamine and SMO can impact the function of PTCH-1, thereby influencing the structure of SMO. Perhaps, these signal activities are related to the endogenesis of various small molecules[32].
     As SHH inhibitors were discovered firstly, cyclopamine was explored as a way to suppress SMO activity and arrest the growth of various tumors[33]. BMPCs, especially those that play a critical role in cancer angiogenesis and tumor growth, are targeted by SHH paracrine secretion. Cyclopamine not only weakens the recruitment of BMPCs into cancer cells, but also reduces the formation of tumor vasculature. Angiopoietin-1 initiates and maintains the vascular system of the pulmonary branches that are regulated by SHH, while the expression of angiopoietin-1 mRNA in the fibroblasts can be increased by SHH; however, the expression of angiopoietin-2 can also be decreased[34]. Partial BMPCs expresseing Tie-2 receptor assist in the promotion of autocrine and paracrine related to angiogenic activities via the process that angiopoietin-1 ligand embraces the matrix material[35]. The cancerous vascular system becomes unstable after treatment with cyclopamine because of the expression of angiopoietin-1 in the matrix, which is under the regulation of SHH, and because insulin-like growth factor-1 (IGF-1) is suppressed. Vascular endotheliocytes express Tie-2, and a subgroup of angiogenic cell precursors can be stabilized by angiopoietin-1 in the microenvironment of tumors. Meanwhile, angiopoietin-1 mRNA in BMPCs can be up-regulated by the soluble factor, KP-1N, in cells that depend on SMO activity.
     SHH signaling is involved in the paracrine regulation of tumor growth. Platelet-derived growth factor-B (PDGF-B) expression is down-regulated after treatment with cyclopamine in xenograft cancer models; this may be related to the reduction of pericells in neogenic vessels[36]. SHH also directly stimulates the proliferation and metastasis of BMPCs; in addition, it also induces the generation of the angiogenic factors that promote vascular remodeling. The factors that influence pancreatic cancer cells may increase the metastatic ability of the precursors affected by SMO, and the SHH signals that act on the vessel endothelium may activate BMPCs to generate an asynergistic effect with the developed vessel endotheliocytes. SHH signaling promotes the generation of capillary vessels and the activities of precursors via the venous endotheliocytes of the human umbilical cord[37].
     Based on a previously reported study performed using chick embryos, cyclopamine may promote the generation and growth of pancreatic tissue[38]. In another experiment that utilized pancreatic cancer orthotopic grafts in rats, only one of seven rats treated with cyclopamine developed mild lung metastasis, and the seven rats in control group developed cancer metastases in multiple organs. This study also demonstrates that the combination of cyclopamine and gemcitabine is able to suppress tumor metastases in vivo as well as reduce the volume of primary tumors[33]. Researchers[19] at Johns Hopkins University reported that the median survival time of transgenic pancreatic cancer rats was prolonged from 61 to 67 d and carcinomatous metastasis was suppressed after treatment with cyclopamine. Another report published by Johns Hopkins University demonstrates that the aberrant expression of IHH, as well as the SHH pathway, can be detected in gastrointestinal cancers that originate from the pancreas; furthermore, SMO-targeting inhibitors of HH not only restrain the growth of tumor cells in vitro, but also block the growth and metastasis of tumor xenografts in vivo[39]. These findings indicate that it is effective to treat pancreatic cancer by prohibiting SMO activity and inhibiting the deregulation of SHH signaling. The investigators treated 125 cell lines with SMO inhibitors and their results indicate that the activity of the HH signal has no direct effect on the inhibitors, perhaps because the HH signals that are secreted by cancerous tissues affect interstitial cell SMO proteins and result in the growth of tumor frame construction, transformation of the extracellular matrix, and the release of various interstitial cell factors such as Wnt and IGF[40].
     It is becoming increasingly important to discover new and effective antagonists against SMO via screening methods as well as the chemical modification of cyclopamine derivatives. There are a few SMO antagonists, such as IPI-926, XL-139, and PF-04449913 being expected to become standard pancreatic cancer treatments[41]. GDC-0449 was the first SMO antagonist to be studied in clinical trials. In a phase Ⅰ clinical trial, 68 tumor patients were enrolled. Among these, 33 cases of basal cell carcinoma (55%) demonstrated a clinical response and two cases demonstrated complete remission. The adverse effects of this antagonist were mild, but included anorexia, alopecia, marasmus, and hyponatremia[42]. In another phase Ⅰ clinical trial on GDC-0449, 19 tumor cases were enrolled, divided into three groups, and administered 150, 270 or 540 mg/d GDC-0449, respectively. Adverse effects, including hyponatremia, were noted in the 540 mg/d group, especially hypodynamia (though one case was noted in each group). In the 150 mg/d group, one case of basal cell carcinoma demonstrated a partial response to treatment; in the 270 mg/d group, one case of basal cell carcinoma and one case of adenoid cystic carcinoma were stabilized. The results of the cutis biopsies performed on the 11 cases in this study demonstrated that the expression level of Gli1 decreased by more than two-fold, and the safety of the 150 mg/d oral dose demonstrated favorable pharmacodynamics and pharmacokinetics[43]. However, in a phase Ⅱ clinical trial on GDC-0449 that was performed in Europe, no benefits were detected in the treated patients[44]. Phase Ⅰ and Ⅱ clinical trials have already been performed to determine the effectiveness of GDC-0449 for treating pancreatic cancer[45,46], but no results have been reported. LDE225 is an SMO antagonist that was tested in a phase Ⅰ clinical trial. In the reported trial, 25 patients with tumor were divided into four groups and administered 100, 200, 400 or 800 mg/d LDE225, respectively. Among these groups, tolerance for this drug was verified and no toxic dose limit was indicated; moreover, one patient of medulloblastoma demonstrated a partial response that included favorable pharmacodynamics and pharmacokinetics. The adverse effects included hypodynamia, nausea, vomiting, anorexia, muscle spasms, and dysgeusia[33].


4  Discussion
SMO-targeting therapies that affect the HH signaling pathway bring new hope to pancreatic cancer patients. SMO-targeting therapies may inhibit the transduction of HH signaling, increase the curative effects of cell toxicity and chemotherapeutic drugs, and inhibit fibroplasia in tumors. Furthermore, SMO-targeting therapies are able to decrease the proportion of cancer stem cells in tumor cell groups and inhibit the growth mechanisms of cancer stem cells, ultimately resulting in the arrest of tumor growth[46,47]. Gemcitabine is a first-line medicine for treating pancreatic cancer, but the clinical prognosis and survival time of treated patients have not been shown to be affected by this drug. According to current theories regarding cancer stem cells, the existence and actions of cancer stem cells could lead to various therapies to fail, including chemotherapy. The SHH expression levels of pancreatic cancer stem cells are higher than those recorded in normal pancreatic cells. The SMO protein acts as a bridge in the SHH signaling pathway, and treatment with SMO antagonists may induce pancreatic cancer stem cells to lose the characteristic traits of stem cells; therefore, SMO is a prospective treatment that could be used to target pancreatic cancer cells. Several SMO antagonists have been studied in clinical trials and their curative effects have been verified, but determining the proper way to use them clinically requires further research. In the meantime, some reports indicate that SMO can generate the ideal oncotherapeutic effects that antagonize the activities of Gli, which is located lower than SMO in the SHH pathway[48,49]. As the classical SMO antagonist, cyclopamine is an alkaloid that can be extracted from V. Californicum by Western scholars using the techniques of traditional medicine. The use of herbal medicine is very common in traditional Chinese medicine, and perhaps Chinese researchers may be able to explore more effective SMO-targeting drugs in the future.


5  Competing interests
The authors have no conflicts of interest to declare in regard to this study.

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