基底细胞癌中肿瘤相关信号通路研究进展

肿瘤的发生、发展、浸润以及转移中均伴随着相关信号通路的信号失调.基底细胞癌是一种最为常见的皮肤恶性肿瘤.大量的研究发现,以Hedgehog信号通路为核心包括wnt、表皮生长因子受体、Notch、转化生长因子β/骨形态发生蛋白、FasL-Fas、P13K-AKT、促分裂原活化蛋白激酶和核因子-κB等多种信号通路的失调在其肿瘤生物学行为中发挥着重要的作用.更为重要的是,基底细胞癌中Hedgehog信号通路在信号传导途径中与包括wnt、表皮生长因子受体、转化生长因子β/骨形态发生蛋白和Notch等信号通路存在着交联机制.这些信号通路的研究对于更加深入地揭示基底细胞癌的肿瘤发生发展机制及寻找更加准确的药物治疗靶点具有重要的意义.

Abstract：

Deregulation of signaling pathways is commonly accompanied with the initiation, development,infiltration and metastasis of many kinds of tumors.Basal cell carcinoma(BCC)is a most common form of skin malignancy.Numerous studies have shown that many signaling pathways including Wnt, epidermal growth factor receptor(EGFR), Notch, transforming growth factor(TGF)β/bone morphogenetic protein(BMP), FasL-Fas, PI3K-AKT, mitogen-activated protein kinase(MAPK), nuclear factor kappa B, etc, play an essential role in the biological behaviors of BCC.Of these signaling pathways, Hedgehog is the core pathway.Most importantly, there are some cross-talks between Hedgehog pathway and Wnt, EGFR, TGFβ/BMP, Notch pathway in the signal transduction in BCC.Researches on these signaling pathways in BCC may contribute to the illumination of pathogenesis of BCC and searches for accurate therapeutic targets.     

Patched 1 expression in Merkel cell carcinoma

The relevance of Hedgehog signaling in Merkel cell carcinoma has only been addressed by a few studies with conflicting results. Thus, we aimed to establish the expression of Hedgehog signaling molecules in Merkel cell carcinoma to characterize causes of aberrant expression and to correlate these findings with the clinical course of the patients. Immunohistochemistry was performed for Sonic, Indian, Patched 1 (PTCH1) and Smoothened on patients’ tumor tissue. Respective mRNA expression was analyzed in 10 Merkel cell carcinoma cell lines using quantitative real‐time polymerase chain reaction. PTCH1 sequencing and DNA methylation microarray analyses were carried out on tumor tissues as well as cell lines. PTCH1 immunoreactivity in Merkel cell carcinoma was similar to that of basal cell carcinomas, which both significantly differed from PTCH1 immunoreactivity in healthy skin. Most PTCH1 mutations found were synonymous or without known functional impact. However, on average, the promoter regions of both PTCH1 were hypomethylated independently from PTCH1 gene expression or Merkel cell polyomavirus status. PTCH1 and GLI1/2/3 genes were differently expressed in different cell lines; notably, there was a significant correlation between GLI2 and PTCH1 mRNA expression. Similar to PTCH1 protein expression in patient tissues, PTCH1 gene expression in Merkel cell carcinoma cell lines is highly variable, but due to the similar methylation pattern across Merkel cell carcinoma cell lines, effects other than methylation seem to be the reason for the differential expression and PTCH1 appears to be upregulated by GLI as a classical Hedgehog target gene.     

Topical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor

Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs in NBCCS. LDE225, a distinct, selective antagonist of SMO, showed potent inhibition of basaloid tumor nest formation and mediated regression of preformed basaloid tumors in organ cultures of skin derived from Ptch1 heterozygous knockout mice. In a double-blind, randomized, vehicle-controlled, intraindividual study, a total of 8 NBCCS patients presenting 27 BCCs were treated twice daily with 0.75% LDE225 cream or vehicle for 4 weeks. Application of 0.75% LDE225 cream was well tolerated and showed no skin irritation. Of 13 LDE225-treated BCCs, 3 showed a complete, 9 a partial, and only 1 no clinical response. Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Treatment with 0.75% LDE225 cream in NBCCS patients was very well tolerated and caused BCC regression, thus potentially offering an attractive therapeutic alternative to currently available therapies for this indication.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.     

基底细胞癌的分子遗传机制研究进展

基底细胞癌是一种最为常见的皮肤癌。近年来研究表明,SHH信号通路的变异在基底细胞癌的发生中起到一个关键的作用,SHH通路的重要成员包括SHH、PTCH1、SM0、GLI,SHH的失调与细胞的PTCH1基因突变相关,SMO的过度激活和转录因子GLI的异常导致多种细胞生长和增殖的基因转录表达上调,并促进了基底细胞癌的形成。SHH信号通路抑制剂对肿瘤的抑制作用为基底细胞癌的治疗提供了一个新的策略。     

First‐in‐human trial of nanoelectroablation therapy for basal cell carcinoma: proof of method

This nanoelectroablation therapy effectively treats subdermal murine allograft tumors, autochthonous basal cell carcinoma (BCC) tumors in Ptch1+/‐K14‐Cre‐ER p53 fl/fl mice, and UV‐induced melanomas in C57/BL6 HGF/SF mice. Here, we described the first human trial of this modality. We treated 10 BCCs on three subjects with 100–1000 electric pulses 100 ns in duration, 30 kV/cm in amplitude, applied at 2 pulses per second. Seven of the 10 treated lesions were completely free of basaloid cells when biopsied and two partially regressed. Two of the 7 exhibited seborrheic keratosis in the absence of basaloid cells. One of the 10 treated lesions recurred by week 10 and histologically had the appearance of a squamous cell carcinoma. No scars were visible at the healed sites of any of the successfully ablated lesions. One hundred pulses were sufficient for complete ablation of BCCs with a single, 1‐min nanoelectroablation treatment.     

Evidence that superficial basal cell carcinoma is monoclonal from analysis of the Ptch1 gene locus

BACKGROUND: Superficial basal cell carcinoma (BCC) arises as an apparently multifocal proliferation of tumour nests attached to the epidermis, which is at odds with a monoclonal origin. Computer-assisted reconstruction shows that these nests join in three dimensions, but it remains unknown whether this tumour is monoclonal. An early event in BCC formation, loss of heterozygosity (LOH) at the Patched 1 (Ptch1) locus, can be used as a tool to address whether this tumour is monoclonal. OBJECTIVES: To determine whether superficial BCC is monoclonal by analysing individually microdissected superficial BCC nests and looking for the same pattern of LOH in each. METHODS: Six cases of superficial BCC were analysed for LOH at the Ptch1 gene locus using the D9S287 microsatellite marker. Identical allelic patterns were sought in each nest from a given tumour. These patterns were no allelic loss, loss of the shorter allele or loss of the longer allele, each with a respective probability of occurrence, as estimated from published findings. RESULTS: All cases were informative. Four cases showed no LOH in each nest and two showed loss of the same allele. If these nests arose independently, then the probability of this result was between 4 x 10-11 and 2 x 10-14. The lack of LOH, seen in four cases, could be due to monoclonal expansion of a cell retaining both D9S287 alleles, or due to a polyclonal proliferation. Therefore, a separate analysis excluding these cases was done, giving a probability of between 2.2 x 10-4 and 1.0 x 10-7. CONCLUSIONS: These probabilities were so extreme that it was unlikely that the nests arose independently, thus providing the first molecular evidence that superficial BCC is monoclonal.     

Multiple lesions of granular cell basal cell carcinoma: a case report

Granular cell change in basal cell carcinoma (BCC) occurs rarely. Only 11 such cases have been reported; all of them were solitary nodular BCC. We report herein a case of multiple granular cell BCC with infundibulocystic features. The tumors presented as papules on the anterior neck of a 44‐year‐old female with a prior history of a well‐differentiated squamous cell carcinoma (SCC) of the tongue and radiation involving the area in which BCC developed. Microscopically, the tumors were circumscribed small dermal nodules composed of epithelial cords with granular eosinophilic cytoplasm and entrapped infundibular keratocysts. Given the eosinophilic appearance of the tumor, history of SCC and the lesions multiplicity, the initial biopsy was first interpreted as metastatic SCC. The correct diagnosis of granular cell BCC was established upon rereview of the slides at a cancer center. Given the diagnostic controversy, immunohistochemical stains were performed. The tumor cells expressed Ber‐EP4, CD63 (NKI/C3) and CD68. The tumors were compared to the prior SCC finding different morphologies. Extensive clinical evaluation showed no evidence of recurrent SCC. This report expands the clinicopathologic spectrum of granular cell variant of BCC and documents for the first time eruption of multiple such tumors in a localized area.     

皮肤鳞状细胞癌皮损和细胞系中Patched-1及Gli-1表达的检测

目的探讨Hedgehog信号传导通路中Pathched-1(Ptch-1)和Gli-1在鳞状细胞癌皮损和细胞系中的表达情况及其意义。方法采用免疫组化技术分别检测鳞状细胞癌皮损和细胞系A431、HSQ-89、HSC-2及Tca中Hedgehog信号通路的Ptch-1及Gli-1的蛋白水平的表达与分布。结果Ptch-1及Gli-1在鳞癌皮损、细胞系A431、HSQ-89以及HSC-2细胞中均有阳性表达,主要分布在鳞癌细胞胞膜及胞浆中。结论鳞癌皮损和细胞系中Ptch-1及Gli-1的阳性表达可能通过激活Hedgehog信号传导通路,促进鳞状细胞癌的形成和发展。     

Correlations between the Sonic Hedgehog pathway and basal cell carcinoma

The Hedgehog (HH) family of intercellular signaling proteins has some essential functions in patterning both invertebrate and vertebrate embryos. Identified as an important regulator of segment polarity and tissue organization in flies, the HH pathway can also play a significant role in human development and in cutaneous carcinogenesis. The family received their name because when the D. melanogaster HH protein malfunctions the mutant fly ends up looking like a small prickly ball, similar to a curled up hedgehog. The Sonic hedgehog (SHH) pathway is implicated in the etiology of the most common human cancer, the basal cell carcinoma (BCC). Mutations in the receptor of SHH, the patched gene (PTCH), have been characterized in sporadic BCCs as well as those from patients with the rare genetic syndrome nevoid BCC. Human PTCH is mutated in sporadic as well as hereditary BCCs, and inactivation of this gene is probably a necessary if not sufficient step for tumorigenesis. Delineation of the biochemical pathway in which PTCH functions may lead to rational medical therapy for skin cancer and possibly other tumors.     

Telomerase activity of Merkel cell carcinomas and Merkel cell carcinoma-derived cell cultures

Abstract Merkel cell carcinomas are rare malignant tumors of the skin, which are predominantly observed in elderly patients (mean age 65–70 years). It is believed but not yet proven that these tumors are derived from the Merkel cells of the epidermis and hair follicles. The Merkel cells themselves probably originate from an asymmetric cell division of basal keratinocytes and the resulting differentiated Merkel cells have presumably, at least in humans, lost their growth potential. The capability of indefinite cell division in germ line cells and in the great majority of malignant tumors as well as an increased growth potential in certain somatic cells (such as basal cells of renewable tissues) is correlated with cellular telomerase activity, which is absent in differentiated somatic cells. In this study the telomerase activity in cryostat sections of frozen Merkel cell tumor biopsies and in in vitro cultivated Merkel cell carcinoma cells was analyzed. We detected telomerase activity in four tumors and three of four cell cultures. These results show that despite their pronounced neuroendocrine differentiation and their occurrence in patients of advanced age, Merkel cell carcinomas possess telomerase activity similar to that of common carcinoma types. Received: 18 October 2000 / Revised: 3 February 2001 / Accepted: 27 April 2001     

BerEP4‐negative basal cell carcinoma on the palm: case report and review of the literature

Only 10 cases of patients with isolated basal cell carcinoma (BCC) of the palms and soles have been published. We describe a patient with an isolated basal cell carcinoma of the palm. Our patient denied injury and exposure to noxious agents; he did not have basal cell nevus syndrome. The tumor was negative for EpCAM as determined by BerEP4 immunohistochemistry, although EpCAM expression usually is seen in BCC in more conventional locations. Because the tumor cells were connected to secretory eccrine glands, we speculate that BCC of the palm originates from common progenitor cells of eccrine glands or epidermal stem cells. We review the literature on these rare BCC in atypical anatomical regions, and discuss the cellular origin of BCC in such locations.     

Neuroendocrine differentiation in basal cell carcinomas: a retrospective immunohistochemical and ultrastructural study

Recent investigations have suggested that in addition to basaloid cells, basal cell carcinomas (BCC) may also contain Langerhans cells and neuroendocrine cells. In order to establish the relative frequency of neuroendocrine differentiation in BCC, we performed a retrospective study of 50 consecutive BCC using conventional histochemical, immunocytochemical and ultrastructural methods. Argyrophil staining according to Grimelius was used for initial identification. Tumors containing argyrophil cells, as well as randomly selected tumors without these cells, were immunocytochemically stained with a panel of antisera against neurohormonal peptides. Only 2 tumors with argyrophil cells showed occasional somatostatin immunoreactivity; peptide hormone immunoreactivity could not be detected in any of the others. The somatostatin immunoreactive tumors, as well as 3 others, were subjected to electronmicroscopy to study the presence of dense-core secretory granules. However, these characteristic intracytoplasmatic structures could be detected in none. It is concluded that if neuroendocrine differentiation exists at all in BCC, it must be extremely rare. Our results indicate that reliable identification of multiple lines of differentiation in neoplasms can only be performed using combinations of (immuno) histochemical and ultrastructural techniques.     

皮肤基底细胞癌和皮肤鳞状细胞癌270例回顾性分析

 目的:总结我院皮肤基底细胞癌(BCC)和皮肤鳞状细胞癌(SCC)临床与组织病理资料,以期提高BCC与SCC的诊断率。方法：回顾性分析2014年1月1日-2018年12月31日间我院皮肤科门诊经组织病理切片确诊的170例BCC与100例SCC患者的临床与病理资料。结果：BCC与SCC年度发病整体均呈逐渐上升趋势。BCC、SCC男女患病比例分别为0.8∶1、1∶1，好发部位均为曝光部位(头面颈部和四肢)，临床诊断与组织病理诊断符合率分别为62.4%与30.0%。临床诊断上，BCC易与脂溢性角化病(SK)、色素痣混淆；SCC易与BCC、鲍温病、光线性角化病(AK)混淆。结论：BCC和SCC为临床常见的非黑素性皮肤肿瘤，但易误诊和漏诊。临床医生对于可疑病灶应尽早行皮损组织病理检查。     

Rippled-pattern basal cell carcinoma

Basal cell carcinoma (BCC) is the most common malignant cutaneous neoplasm, however, there have been few studies on BCC with a "rippled pattern" so far. We reviewed the 650 BCC specimens from the archives of our institution, and only one example of BCC with a rippled pattern was found. We herein report the histopathological characteristics of this case. Within the lesion, which showed the typical histopathological features of nodular BCC, there was a noticeable area composed of 10-15 basaloid aggregations, which showed the rippled pattern. The rippled pattern was characterized by alternating bands of epithelial cords of spindle-shaped basaloid cells and mucinous spaces. Characteristically, around the rippled-pattern area, neoplastic aggregations with a mucinous reticulated or cystic pattern (pseudo-tubular structures), and many cord-like structures were seen. A review of the published work and the present case suggested that the histopathological characteristics of rippled-pattern BCC are: (i) a nodular type of BCC; (ii) considerably rare; (iii) have frequent intervention by mucinous spaces between the epithelial cords; and (iv) no apparent divergent differentiation with folliculosebaceous-apocrine lineage. The last three characteristics contrasted with those of the rippled-pattern sebaceoma/trichoblastoma. However, neoplastic germinative cells in rippled-pattern BCC may naturally form cord-like structures in a manner similar to rippled-pattern sebaceoma/trichoblastoma.     

Dendritic cells in pigmented basal cell carcinoma: a relevant finding by reflectance-mode confocal microscopy

BACKGROUND: Reflectance-mode confocal microscopy (RCM) is a new approach for the in vivo diagnosis of skin tumors. A few studies of RCM on basal cell carcinoma (BCC) have provided specific diagnostic criteria, but large studies on pigmented basal cell carcinoma are lacking. Proliferation of large dendritic-shaped cells within a melanocytic tumor has been associated with the diagnosis of melanoma by RCM. Benign melanocytes and Langerhans cells may populate BCC according to previous histological studies. We studied 3 consecutive pigmented BCC by means of RCM and performed a histological and immunohistochemical correlation focusing on the presence of dendritic structures. OBSERVATIONS: Reflectance-mode confocal microscopy revealed highly refractive dendritic structures within tumor nests that correlated with the presence of melanocytes within the tumor by immunochemical analysis. In 1 case, dendritic structures on the overlying epidermis corresponding to Langerhans cells were also noted. Leaf-like areas observed on dermoscopy correlated with low-refractive cordlike structures and nodules by RCM and corresponded to nests of basaloid cells, whereas blue-gray globules presented as bright oval structures with ill-defined borders corresponding to melanophages. CONCLUSIONS: Reflectance-mode confocal microscopy allows the study of pigmented BCC and the identification of specific criteria described previously. In these tumors, dendritic melanocytes can be easily identified with this technique.     

Immunohistochemical evaluation of basal cell carcinoma and trichepithelioma using Bcl-2, Ki67, PCNA and P53

Most basal cell neoplasms with follicular differentiation represent a heterogenous group of tumors. Although may arise anywhere in the skin, these neoplasms commonly occur on the head and neck regions. The majority of these neoplasms are basal cell carcinomas (BCC) and trichoepitheliomas (TE). Overlapping histopathologic features between these benign and malignant tumors are occasionally seen which may create problems in rendering a definitive diagnosis. The intent of this investigation was two-fold: 1) to examine whether there are quantitative differences of the cellular expression of Bcl-2, Ki67, PCNA and P53 between BCC and TE; and 2) to examine the value of these immunostains in differentiating between BCC and TE. Twenty cases of BCC were stained with antibodies for Bcl-2, Ki67, PCNA and P53. The positive cell indices and staining characteristic of these immunostains were compared with those of 20 cases of TE. The cell indices for each group were analyzed statistically utilizing the analysis of variance (ANOVA) technique. Intensity and patterns of Bcl-2 and P53 expression were similar between BCC and TE. The ANOVA analysis showed no statistically significant differences between cell indices for cases stained with antibodies for Bcl-2 and P53 (p=0.49 and p=0.87 respectively) in the two neoplastic groups. There were intense labelling and generalized patterns of Ki67 and PCNA expression in BCC. Conversly, Ki67- and PCNA-labelled cells were much fewer in TEs than those noted in BCCs. Additionally, Ki67- and PCNA-positive cells were limited to the peripheral layers of the neoplastic islands of TEs. There were statistically significant differences between cell indices for cases stained with antibodies for Ki67 and PCNA (p=0.02 and p=0.05 respectively) in the two neoplastic groups. BCC and TE exhibited comparable expressions of Bcl-2 and P53 with similar intensity of labelling and patterns of distribution. This suggests possible similar mechanisms of growth regulation in both neoplasms. However, Ki67 and PCNA labelling was noted with significantly increased numbers and recognizably different patterns in BCCs compared to TEs. This may help explain the significant capabilities in tumor proliferation and the aggressive behavior of BCC compared to the limited growth potential of TE. Additionally, Ki67 and PCNA staining intensity and characteristics may have some value in differentiating between BCC and TE.