Abnormal expression of G71 antibody at the epidermal basement membrane in basal cell carcinoma.

The antibody G71 is a murine monoclonal antibody directed against an antigen in the basement membrane zone of many human epithelia. Ultrastructurally it is located in the lamina lucida. The epitope is carried on glycoprotein components with molecular weights of 160, 125 and 115 kilodaltons. The authors examined the immunohistochemical expression of G71 antigen, using a standard indirect immunoperoxidase technique, in benign and malignant tumors derived from the epidermis. G71 staining was consistently absent or reduced around basal cell carcinomas (n = 44). In contrast, G71 was present at the basement membrane zone of squamous cell carcinomas (n = 18) and was also frequently expressed within the cytoplasm and on the cell surface of the malignant keratinocytes. The staining pattern of G71 at the basement membrane zone was essentially normal in keratoacanthomas (n = 10), solar keratoses (n = apart from foci of attenuation. In both seborrheic keratoses and intraepidermal squamous 13), seborrheic keratoses (n = 6), and intraepidermal squamous cell carcinomas (n = 8), cell carcinomas cell-surface and cytoplasmic staining were inconstant features. In conclusion, there appears to be a specific defect of G71 antigen expression in basal cell carcinomas.     

Invasion of reconstituted basement membrane matrix is not correlated to the malignant metastatic cell phenotype

Interactions between tumor cells and basement membranes represent a critical step in the progression of neoplasia and in the metastatic process. Reconstituted basement membrane matrix, matrigel, has been recently used with the aim of developing an in vitro assay of tumor cell invasiveness. We have extended these studies by comparing the invasiveness of a large series of normal and malignant epithelial and mesenchymal cells of human and animal origin cultured on matrigel. Normal cells (fibroblasts, glomerular mesangial cells, keratinocytes), human fibrosarcoma cells (HT1080), and reticular sarcoma cells (M5076) clearly established invasive capabilities in the matrix. However, all the other tested cell lines, malignant or virally transformed cells invasive in vivo (MCF7, T47D, SA52, SW613, MO4, A431, BeWo), as well as normal nontransformed cells (MOH22) were incapable of penetration. The morphological features of matrigel invasion by normal fibroblasts and HT1080 cells are described at the light and electron microscope levels. The extent of degradation of a radiolabeled matrigel is minimal and similar in several cell lines reported to be noninvasive or invasive in vivo. Our data suggest that matrigel does not provide a universal model to correlate the invasiveness of cells in vivo and in vitro.     

The association of basal cell carcinomas with other tumors

We report the case of a patient who had a lesion on the back that clinically resembled a basal cell carcinoma, but histologically showed changes of a basal cell carcinoma and a nodular malignant melanoma. We also review the literature on the association of basal cell carcinomas with other tumors.     

The epidermal growth factor receptor is required to maintain the proliferative population in the basal compartment of epidermal tumors

Previous studies using keratinocytes from epidermal growth factor receptor (EGFR)-deficient mice revealed that the EGFR is not required for papilloma formation initiated by a mutant rasHa gene, although the tumors that develop are very small (A. A. Dlugosz et aL, Cancer Res., 57: 3180-3188, 1997). The current study used a combination of bromodeoxyuridine pulse-chase, proliferating cell nuclear antigen distribution, and differentiation marker analysis to reveal the following: (a) the EGFR was required to maintain the proliferative population in the basal cell compartment of papillomas; (b) in the absence of EGFR, cycling tumor cells migrated into the suprabasal compartment and initiated the differentiation program prematurely; and (c) these changes were associated with cell cycle arrest. Further analysis of v-rasHa-transformed EGFR-deficient keratinocytes in vitro indicated that such cells migrated more on and attached less to extracellular matrix components. Together, these studies reveal that an essential function for the EGFR pathway in squamous tumors is to maintain a proliferative pool of basal cells and prevent premature terminal differentiation.     

口腔癌基底膜改变的观察

目的　观察口腔鳞状细胞癌基底膜的Ⅳ型胶原表达及超微结构改变。方法　 46例口腔癌标本采用免疫组化方法染色观察Ⅳ型胶原的表达 ,其中 3例标本采用透射电镜 (TEM )进行了超微结构观察。结果　在肿瘤周围的正常粘膜内 ,Ⅳ型胶原阳性表达且呈连续的线状分布。在癌组织中 ,分化差及伴有淋巴结转移的病例中 ,Ⅳ型胶原表达弱甚至无表达 ,但在某些分化较好的部位 ,可发现其表达增强。超微结构观察结果显示 :在胶原纤维完整 ,上皮下结缔组织内成纤维细胞丰富、功能活跃部位 ,基底膜较完整 ,相应部位之上皮细胞分化较好。相反 ,上皮下结缔组织内胶原纤维溶解破坏 ,基底膜破损部位以及成纤维细胞稀少部位 ,上皮细胞分化较低。结论　 (1)Ⅳ型胶原表达反映了恶性细胞侵袭破坏作用与结缔组织防御修复功能相互作用的结果。 (2 )改变上皮下结缔组织健康状况及抗病能力可能是限制口腔癌发展的有效措施。     

Patterns of epidermal growth factor receptors in basal and squamous cell carcinoma

The presence of immunoreactive epidermal growth factor receptors in human skin tumors was investigated using the indirect immunoperoxidase technique. Sixteen basal cell carcinomas and 11 squamous cell carcinomas were evaluated. All of the specimens studied were receptor positive. In 70% of the specimens there was prominent staining of the cell membranes. In 54% of the nodular basal cell carcinoma specimens there was increased staining at the periphery of the tumor cell masses.     

A basal cell carcinoma of the esophagus--a case report

Reported is the case of a 58-year-old male who visited our hospital with the chief complaint of anorexia. Diagnosed as having an esophageal cancer, a subtotal esophagectomy was performed including the dissection of the tumor. According to the surgical findings, the tumor was not exposed to the tunica externa and no lymph node metastasis or infiltration to the pleura or a metastasis to the lung or liver was note. On histopathological examination a basal cell carcinoma of esophagus was determined but no squamous epithelium was seen. The carcinoma was the muscular propria, and neither infiltration into the epithelium nor invasion into the vessels was noted. The postoperative progress appeared good, however seven months later the patient died from multiple hepatic metastasis.     

The immune system prevents recurrence of transplanted but not autochthonous antigenic tumors after oncogene inactivation therapy

Targeted oncogene inactivation by small molecule inhibitors can be very effective but tumor recurrence is a frequent problem in the clinic. Therapy by inactivation of the cancer‐driving oncogene in transplanted tumors was shown to be augmented in the presence of T cells. However, these experiments did not take into account the long‐term, usually tolerogenic, interaction of de novo malignancies with the immune system. Here, we employed mice, in which SV40 large T (Tag) and firefly luciferase (Luc) as fusion protein (TagLuc) could be regulated with the Tet‐on system and upon activation resulted in tumors after a long latency. TagLuc inactivation induced profound tumor regression, demonstrating sustained oncogene addiction. While tumor relapse after TagLuc inactivation was prevented in immunocompetent mice bearing transplanted tumors, autochthonous tumors relapsed or recurred after therapy discontinuation indicating that the immune system that coevolved with the malignancy over an extended period of time lost the potency to mount an efficient anti‐tumor immune response. By contrast, adoptively transferred CD8⁺ T cells targeting the cancer‐driving oncogene eradicated recurrent autochthonous tumors, highlighting a suitable therapy option in a clinically relevant model.     

Urinary tuberculosis is associated with the development of urothelial carcinoma but not renal cell carcinoma: a nationwide cohort study in Taiwan

Background:

Obstructive uropathy and chronic urinary tract infection increase the risk of urinary tract cancer. Urinary tuberculosis (UTB) can cause chronic urinary tract inflammation, lead to obstructive uropathy, and potentially contribute to the development of urinary tract cancer. However, the association between UTB and urinary tract cancer has not been studied.

Methods:

This study enrolled 135 142 tuberculosis (TB) cases (male, 69%) from a nationwide health insurance research database in Taiwan and investigated the risk factors for urinary tract cancer, with emphasis on a history of UTB. The incidence of urinary tract cancer in the general population without TB was also calculated for comparison.

Results:

The TB patients had a mean age of 57.5±19.5 years. Of the 1287 UTB and 133 855 non-UTB patients, 15 (1.2%) and 396 (0.3%) developed urothelial carcinoma, respectively (P<0.001); and 2 (0.2%) and 96 (0.1%) developed renal cell carcinoma, respectively (P=0.240). Cox regression analysis revealed that age, male sex, end-stage renal disease, obstructive uropathy, arsenic intoxication, organ transplantation, and UTB (hazard ratio: 3.38 (2.01–5.69)) were independent risk factors for urothelial carcinoma. The hazard ratio of UTB was higher among female patients (5.26 (2.12–13.06)) than that among male patients (2.96 (1.57–5.60)).

Conclusion:

Urinary tuberculosis had a strong association with urothelial carcinoma, but not with renal cell carcinoma. In TB endemic areas, the urinary tract of TB patients should be scrutinised. It is also imperative that these patients be followed-up carefully in the post-treatment period, and urinalysis, ultrasonography or endoscopy should be an integral part of the follow-up.     

Distribution of basement membrane components in human hepatocellular carcinoma

The distribution of fibronectin (FN), laminin (LAM), and collagen IV (Coll IV), three components of the basement membranes (BM), was investigated in human hepatocellular carcinoma (HCC) and the surrounding uninvolved liver and was compared with the grade of differentiation of the tumor. The following three patterns of BM antigens were observed in HCC: (1) peritrabecular or periacinar, (2) pericellular, and (3) stromal-vascular. In the more differentiated tumors, FN, LAM, and Coll IV were observed in a peritrabecular or periacinar pattern whereas a pericellular pattern was only seen with anti-FN antisera that occasionally stained the content of acini. Double staining showed that the four antigens were usually codistributed. Occasionally, however, there was a different distribution along the BM suggesting an heterogeneity in the composition of BM. In the more anaplastic tumors and in the intrahepatic metastasis, BM components were seen around vessels and in the stroma and they were usually fragmented. The finding that FN can be located pericellularly or within acini supports the concept that FN is synthesized, at least in part, by hepatoma cells. The peritrabecular and periacinar location of Coll IV and LAM suggests a sinusoidal cell derivation of these two antigens. The immunohistochemical staining patterns for BM in HCC reflect the differentiation of the tumor, with differentiated tumors showing a relatively intact BM and poorly differentiated tumors showing a sharply defective BM.     

Integrin beta1 is required for the invasive behaviour but not proliferation of squamous cell carcinoma cells in vivo

Integrin beta1 is both overexpressed and in an 'active' conformation in vulval squamous cell carcinomas (VSCCs) compared to matched normal skin. To investigate the significance of integrin beta1 deregulation we stably knocked-down integrin beta1 expression in the VSCC cell line A431. In vitro analysis revealed that integrin beta1 is required for cell adhesion, cell spreading and invasion. However, integrin beta1 is not required for cell growth or activation of FAK and ERK signalling in vitro or in vivo. Strikingly, while control tumours were able to invade the dermis, integrin beta1 knockdown tumours were significantly more encapsulated and less invasive.     

Syndecan-1 expression is up-regulated in pancreatic but not in other gastrointestinal cancers

Syndecan-1 belongs to the syndecan family of cell surface transmembrane heparan-sulfate proteoglycans, which participate in cell proliferation, cell migration and cell-matrix interactions. Decreased expression of syndecan-1 has been observed in some gastrointestinal malignancies, and it is thought that high levels of syndecan-1 correlate with the maintenance of epithelial morphology and inhibition of invasiveness. In our study, we characterized the expression of syndecan-1 in normal, chronic pancreatitis and primary and metastatic human pancreatic cancer tissues, in cultured pancreatic cancer cell lines and in esophageal, gastric, colon, and liver cancers. Pancreatic cancer cell lines expressed syndecan-1 mRNA and protein at variable levels. In addition, these cells also released syndecan-1 into the culture medium. Pancreatic cancer tissues markedly over-expressed syndecan-1 mRNA in comparison with both chronic pancreatitis (2.4-fold increase, p < 0.01) and normal pancreatic samples (10.6-fold increase, p < 0.01). There was no difference in syndecan-1 mRNA expression between early and advanced tumors. By in situ hybridization and immunohistochemistry, syndecan-1 expression was evident at relatively low levels in the ductal cells and less frequently in acinar cells of the normal pancreas. In chronic pancreatitis, syndecan-1 was present at low to moderate levels in areas with atrophic acinar cells and ductular complexes. In contrast, in pancreatic cancer tissues, syndecan-1 was present at moderate to high levels in the majority of the cancer cells within the tumor mass and also in metastatic lesions of pancreatic tumors. Syndecan-1 mRNA levels in other gastrointestinal malignancies (esophageal, gastric, colon and liver cancers) were not significantly different from the levels observed in the corresponding normal samples. Together, our findings suggest that syndecan-1 expression by pancreatic cancer cells may be of importance in the pathobiology of this disorder and that its role in pancreatic cancer seems to be different from that in other gastrointestinal malignancies.     

c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma

We have investigated the role of individual members of the Raf/Mek/Erk cascade in the onset of K-Ras oncogene-driven non-small cell lung carcinoma (NSCLC). Ablation of Erk1 or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet, elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mek kinases. Ablation of B-Raf had no significant effect on tumor development. However, c-Raf expression was absolutely essential for the onset of NSCLC. Interestingly, concomitant elimination of c-Raf and B-Raf in adult mice had no deleterious consequences for normal homeostasis. These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention.     

Intrinsic basal cell carcinoma of the tympanum

Basal cell carcinoma of the tympanum is a rare tumour. This is a slow growing locally malignant tumour. A case of an intrinsic type is reported along with a brief review of the literature.     

Localization of collagenase at the basal plasma membrane of a human pancreatic carcinoma cell line

We have recently presented biochemical evidence for collagen and gelatin degrading activities associated with plasma membranes of various human cancer cell lines. In this report we describe the localization of interstitial collagenase at the basal plasma membrane of the human pancreatic cancer cell line RWP-I, using immunofluorescence and ultrastructural immunogold labeling techniques. Collagenase was expressed on the extracellular face of the plasma membrane. Furthermore, the immunogold labeling was concentrated on the long, finger-like microvillous projections typically seen on the basal cell surface, while the short, brush-like projections characteristic of the apical cell surface were unlabeled. When the cytoplasmic face of the membrane was made accessible, the number of reactive sites increased markedly, indicating a high concentration of enzyme at the inner surface of the plasma membrane. When plasma membrane fractions of RWP-I cells were prepared by differential centrifugation, high salt washes virtually failed to extract collagenase activity from the membrane, while detergent extraction with n-octyl glucoside, a detergent used in the purification of integral membrane proteins, yielded soluble collagenase activity. When detergent extracted membrane fractions were passed over an anticollagenase immunoaffinity column, collagenase was specifically bound, as demonstrated by the TCA and TCB degradation of type I collagen by the bound material. Gelatinolytic activity did not bind to the column. Furthermore, immunoprecipitation of 125I-labeled detergent extracts of tumor membranes yielded a single Mr 55,000 band consistent with the zymogen form of the connective tissue collagenase. These morphological and biochemical findings suggest that collagenase is a tightly associated component of the basal plasma membrane, where it occupies a strategic location for directional proteolysis during cell migration and invasion.