The utility of hedgehog signaling pathway inhibition for cancer

The Hedgehog (Hh) signaling pathway has been implicated in tumor initiation and metastasis across different malignancies. Major mechanisms by which the Hh pathway is aberrantly activated can be attributed to mutations of members of Hh pathway or excessive/inappropriate expression of Hh pathway ligands. The Hh signaling pathway also affects the regulation of cancer stem cells, leading to their capabilities in tumor formation, disease progression, and metastasis. Preliminary results of early phase clinical trials of Hh inhibitors administered as monotherapy demonstrated promising results in patients with basal cell carcinoma and medulloblastoma, but clinically meaningful anticancer efficacy across other tumor types seems to be lacking. Additionally, cases of resistance have been already observed. Mutations of SMO, activation of Hh pathway components downstream to SMO, and upregulation of alternative signaling pathways are possible mechanisms of resistance development. Determination of effective Hh inhibitor-based combination regimens and development of correlative biomarkers relevant to this pathway should remain as clear priorities for future research.     

The utility of the ankle SPECT/CT scan to predict functional and clinical outcomes in supramalleolar osteotomy patients

Combined single‐photon emission computed tomography and conventional computed tomography (SPECT/CT) is a hybrid imaging modality that shows a combination of metabolic and structural information about the ankle, including arthritis. We hypothesize that uptake in specific locations within the ankle joint can be associated with both clinical outcomes and may help predict which patients will have a successful SMO. Eighty‐five pre‐operative SMO patients with varus (37), valgus (41), or neutral (7) alignment of the hindfoot were assessed using SPECT/CT. The level of activation on SPECT/CT scans was measured. Pre and Post‐operative functional scores were recorded. Patients with medial gutter activation had significantly worse (p < 0.05) AOFAS alignment (AOFAS‐A) scores pre‐operatively. Patients with varus or valgus alignment did not have any difference in VAS pain scores, but those in valgus did have worse AOFAS‐P (pain) scores. Those with cystic lesions had a worse FAOS score pre‐operatively. Ten patients (12.5%) had a treatment failure. Pre or post‐operative alignment did not correlate to a treatment failure. The only statistically significant (p = 0.036) poor prognostic indicator was a bipolar lesion. Pre‐operative SPECT/CT evaluation of an ankle before a SMO can be used to clinically correlate patient‐specific factors such as pain and function in the pre and post‐operative period. We caution against performing a SMO in patients with bipolar activation on a pre‐operative SPECT‐CT scan. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2015–2021, 2018.

     

Cervical spine involvement in rheumatoid arthritis — A systematic review

Rheumatoid arthritis (RA) is a systemic chronic inflammatory disorder that can compromise the cervical spine in up to 80% of the cases. The most common radiological presentations of cervical involvement are atlantoaxial subluxation (AAS), cranial settling and subaxial subluxation (SAS). We performed a systematic review in the PubMed Database of articles published later 2005 to evaluate the prevalence, progression and risk factors for cervical spine involvement in RA patients. Articles were classified according to their level of evidence. Our literature review reported a wide range in the prevalence of cervical spine disease, probably explained by the different studied populations and disease characteristics. Uncontrolled RA is probably the main risk factor for developing a spinal instability. Adequate treatment with DMARD and BA can prevent development of cervical instabilities but did not avoid progression of a pre-existing injury. MRI is the best radiological method for diagnosis cervical spine involvement. AAS is the most common form of RA. Long term radiological follow-up is necessary to diagnosis patients with late instabilities and monitoring progression of diagnosed injuries.     

The sonic hedgehog-GLI1 signaling pathway in brain tumor development

Introduction: The sonic hedgehog (Shh) pathway is a regulatory network involved in development and cancer. Proteins like Ptch, SMO, and Gli are central to the Shh pathway. Other proteins like HHIP, SUFU, Bmi-1, Cyclin D2, Plakoglobin, PAX6, Nkx2.2, and SFRP1 are not so well understood in Shh regulation as Gli-1 downstream target genes.

Areas covered: In this review we try to explain the Shh pathway components and their role in development and cancer, mainly of the brain. A summary of each of the proteins is presented together with an overview of their involvement in cancer.

Expert opinion: Genetic alterations of the Shh pathway have been detected in cancer stem cells, a subgroup of tumor cells implicated in the origin and maintenance of tumors, being responsible for cancer recurrence and chemotherapy resistance. Cancer stem cells constitute a novel target for biomedical researchers. Specifically, the Shh pathway is being explored as a new opportunity for targeted therapies against tumors. Therefore, a better knowledge of every of the regulators of the Shh pathway is needed.     

miR-338-3p suppresses invasion of liver cancer cell by targeting smoothened

MicroRNAs are involved in human carcinogenesis and cancer progression. Our previous study has shown that loss of miR-338-3p expression is associated with clinical aggressiveness of hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of miR-338-3p remain unknown in HCC. To determine whether and how miR-338-3p influences liver cancer cell invasion, we studied miR-338-3p in the liver cancer cell lines, and we found that miR-338-3p is down-regulated in treated cells. Forced expression of miR-338-3p in SK-HEP-1 cells suppressed cell migration and invasion, whereas inhibition of miR-338-3p in SMMC-7721 cells induced cell migration and invasion. Furthermore, smoothened (SMO) was identified as a direct target of miR-338-3p. Forced expression of miR-338-3p down-regulated SMO and matrix metalloproteinase (MMP)-9 expression, but inhibition of miR-338-3p up-regulated SMO and MMP9 expression. However, small interfering RNA targeted SMO reversed the effects induced by blockade of miR-338-3p. SMO and MMP9 were overexpressed and associated with invasion and metastasis in HCC tissues. These data indicate that miR-338-3p suppresses cell invasion by targeting the smoothened gene in liver cancer in vitro and miR-338-3p might be a novel potential strategy for liver cancer treatment.     

SMO蛋白及mRNA在食管鳞状细胞癌组织中的表达及意义

目的 探讨SMO蛋白及mRNA在食管鳞状细胞癌组织中的表达及意义.方法 分别应用免疫组织化学及原位杂交方法检测68例食管鳞状细胞癌组织、35例癌旁不典型增生组织及68例正常食管黏膜组织中SMO蛋白及mRNA的表达,并分析其与食管鳞状细胞癌各临床病理特征的关系.结果 SMO蛋白的阳性表达率在正常食管黏膜组织、癌旁不典型增...     

SMO在肾透明细胞癌中的表达

目的 观察肾透明细胞癌(Renal clear cell carcinoma,RCCC)及正常肾组织中SMO 的表达,探讨RCCC中SMO 的异常激活与肾癌之间的关系.方法 采用免疫组织化学技术检测 RCCC 及正常肾组织中SMO蛋白的表达.结果 在正常肾组织中SMO 轻微表达,而在RCCC中SMO 高表达,且其表达与患者的年龄、性别及肿瘤大小均无关.结论 Hedgehog信号通路中SMO 表达上调可能参与了RCC的发病,其在肾细胞癌的发生、发展等方面可能具有重要作用.     

Insight into the molecular pathogenesis of odontogenic lesions

BackgroundOdontogenic tumors, derived from epithelial, ectomesenchymal, and/or mesenchymal elements of the tooth-forming apparatus, constitute a heterogeneous group of lesions, including hamartomas, benign and malignant neoplasms with metastatic capabilities.HighlightThis review provides a comprehensive overviewof the pathogenesis of odontogenic tumors and explains the associated molecular events in the context of hallmarks of cancer established by Hanahan D and Weinberg RA. Diagrammatic representations depicted in the article would facilitate easier understanding.ConclusionA better understanding of the pathogenesis of the lesions may assist in determining patient's prognosis and devising better targeted therapeutic treatment, thus, reducing the morbidity and mortalityof patients.