International Journal of Cancer

Human small‐cell lung‐cancer cells (SCLC) produce and secrete gastrin‐releasing peptide (GRP), the mammalian equivalent of bombesin (BN). There is some evidence to suggest that GRP is an autocrine regulator of SCLC cell growth. In the search for potent BN antagonists, several substance‐P (SP) analogs were found to inhibit the growth of SCLC cells. We found that a known short‐chain SP antagonist, pHOPA‐DTrp‐Phe‐DTrp‐Leu‐Leu‐NH₂ (NY3238), inhibits the binding of ¹²⁵l‐Tyr⁴‐BN on Swiss 3T3 cell line expressing BN receptors, as well as the proliferation of NCI‐H69 SCLC cells. In this study we tested several analogs of NY3238 and we found that NY3521 and NY3460 are more effective in inhibition of proliferation of SCLC cells but less potent in inhibition of binding of ¹²⁵l‐Tyr⁴‐BN on Swiss 3T3 cells than NY3238. Furthermore, we detected specific binding of radiotabelled NY3238 even below I nM on NCI‐H69 cells that could have been inhibited by SP and NY3460 rather than by BN. In addition to these in vitro studies, NY3460 proved to be effective in inhibiting the growth of NCI‐H69 SCLC xenografts in nude mice in vivo. These analogs of NY3238 could be promising therapeutic agents in the treatment of SCLC. © 1995 Wiley‐Liss, Inc.

Metastasis, the life‐threatening aspect of cancer, is a systemic disease process. Considerable progress has been made in recent years regarding how tumor cells circulating in the blood and lymphatic systems interact with and extravasate into secondary sites, and what determines whether these disseminated tumors cells survive, remain dormant or go on to form macrometastases. New insights into the routes that tumor cells take once leaving the primary tumor have emerged. Novel concepts regarding early seeding of metastases coupled to parallel progression, self‐seeding of primary tumors by circulating tumor cells and the induction of premetastatic niches in distant organs by primary tumors have come to the fore. The perceived role of the lymphatic system in determining patterns of metastasis formation in distant organs has been reassessed. Together these new insights have the potential to offer new therapeutic options. In particular, the regulation of tumor cell dormancy emerges as a key event in metastasis formation, and therapeutic control of dormancy holds the promise of rendering cancer a chronic rather than life‐threatening disease.

The roles of the cadherins in the progression of ovarian cancer to the late stages of the disease state when malignant cells have disseminated within the peritoneal cavity remain poorly understood. In view of these observations, we have undertaken a comprehensive survey of the cadherin subtypes present in normal ovarian surface epithelium and peritoneum and in the tumors and peritoneal effusions of women diagnosed with Stage I or Stage II primary ovarian cancer using a degenerate cloning strategy for sequences highly conserved among this family of cell adhesion molecules. On the basis of the nucleotide sequences of the resultant PCR products, multiple cadherin subtypes (E‐, N‐, P‐cadherin, and cadherin‐4, ‐6, and ‐11) were found to be present in these normal and malignant tissues and cells. P‐cadherin was determined to be the predominant cadherin subtype in normal peritoneum, peritoneal effusions and Stage II tumor masses. An increase in P‐cadherin mRNA and protein expression levels in ovarian tumor masses with progression to later stages of the disease state was confirmed by Northern and Western blot analysis, respectively. In addition, we have determined that the cadherin‐associated protein, known as β‐catenin, is expressed in normal peritoneum, ovarian tumors and malignant cell effusions obtained from women with Stage I or Stage II cancer. Immunoprecipitation studies demonstrated that P‐cadherin was capable of interacting with β‐catenin in these normal and malignant tissues and cells. Collectively, these findings suggest that the regulated expression of P‐cadherin/β‐catenin complexes in ovarian tumor cells may represent a key step in disease progression. © 2003 Wiley‐Liss, Inc.

Reactive oxygen species (ROS) have been attracting attention as mediators of various cell‐signaling pathways. Nox‐family NADPH oxidases have proven to be a major source of ROS production in various cell types and have crucial roles in various physiological and pathological processes. In this study, we show that Nox4, a member of Nox family, is prominently expressed in various neuroepithelial tumors by reverse transcription‐polymerase chain reaction (RT‐PCR) and immunohistochemical studies. We quantified Nox4 mRNA expression by real‐time PCR in tumor specimens from 58 patients with astrocytomas and found that the expression levels of Nox4 mRNA in glioblastomas (WHO grade IV) were significantly higher than those in other astrocytomas (WHO grade II and III). In addition, we show that specific knockdown of Nox4 expression by RNA interference results in cell‐growth inhibition and enhances induction of apoptosis by chemotherapeutic agents, such as cisplatin, in cultured glioma cell lines. Based on these observations, enhanced expression of Nox4 appears to be involved in cell proliferation and survival in glioma cells. © 2008 Wiley‐Liss, Inc.

E‐cadherin (E‐cad) plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. This protein exists in two forms: a membrane‐tethered form and a soluble form. Full‐length E‐cad is membrane tethered. As a type I transmembrane glycoprotein, E‐cad mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. Soluble E‐cad (sE‐cad) is the extracellular fragment of the protein that is cleaved from the membrane after proteolysis of full‐length E‐cad. The production of sE‐cad undermines adherens junctions, causing a reduction in cell aggregation capacity; furthermore, sE‐cad can diffuse into the extracellular environment and the blood. As a paracrine/autocrine signaling molecule, sE‐cad activates or inhibits multiple signaling pathways and participates in the progression of various types of cancer, such as breast cancer, ovarian cancer, and lung cancer, by promoting invasion and metastasis. This article briefly reviews the role of sE‐cad in tumorigenesis and tumor progression and its significance in clinical therapeutics.

The development of cervical carcinoma is closely associated with HPV infection. However, other genetic alterations also play an important role. In this study, we analyzed copy number alterations of several oncogene loci in a panel of 84 cervical tumors. Sixty‐five (77%) tumors were HPV DNA‐positive, and most were infected with type 16 or type 18 or both. The oncogenes studied include PIK3CA at 3q26.3, TERT at 5p15.33, C‐MYC at 8q24, CCND1 at 11q13.3, ERBB2 at 17q21.2 and locus region 20q13.2. Amplification of 1 or more genes was detected in 55 (65%) cases using interphase FISH. PIK3CA was amplified in 43% of tumors, followed by TERT (33%), 20q13.2 (30%), ERBB2 (29%), C‐MYC (25%) and CCND1 (12%). Most tumors showed low‐level amplification with 3–7 copies of these genes, and complex changes involving 3 or more genes occur more frequently in tumors at advanced stages. Increased protein expression of c‐erbB2 and c‐myc was observed in tumors with the corresponding gene amplification. Oncogene alterations were found more often in HPV‐infected cases, particularly for C‐MYC and TERT. These findings indicate that HPV‐associated cervical carcinomas bear frequent alterations of these genes, which may have critical biologic impact on the development and progression of carcinoma of the uterine cervix. © 2002 Wiley‐Liss, Inc.

Genomic instability is a hallmark of most human cancers including high‐risk human papillomavirus (HPV)‐associated anogenital neoplasia. The two HPV‐encoded oncoproteins, E6 and E7, can independently induce chromosomal abnormalities. We summarize the current state of knowledge concerning HPV‐induced genomic instability and discuss its significance in the context of human carcinogenesis. © 2003 Wiley‐Liss, Inc.

The genetic and environmental components in 15 common cancers were estimated using the nationwide Swedish Family‐Cancer Database. Tetrachoric correlations were used to describe similarity in cancer liability among family members. Structural equation modeling was used to derive estimates of the importance of genetic and environmental effects. Statistically significant estimates of proportion of cancer susceptibility, accounted for by genetic effects, were obtained for all studied cancers except for leukemia. The estimate was highest in thyroid cancer (53%), followed by tumors at endocrine glands (28%), testis (25%), breast (25%), cervix (22%), melanoma (21%), colon (13%), nervous system (12%), rectum (12%), non‐Hodgkin lymphoma (10%), lung (8%), kidney (8%), urinary bladder (7%), stomach (1%) and leukemia (1%). The estimates of shared environmental effects ranged from 0% (cervix) to 15% (stomach). The childhood shared environmental effects were most important in testicular cancer (17%), stomach cancer (13%) and cervix in situ (13%). Our results indicate that environment has a principal causative role in cancer at all studied sites except for thyroid. The relatively large effect of heritability in cancer at some sites, on the other hand, indicates that even though susceptibility genes have been described at many cancer sites, they are likely to explain only part of the genetic effects. © 2002 Wiley‐Liss, Inc.

Lymphoid cells from many normal mice of a variety of inbred strains were found to have reactivity, in a ⁵¹Cr release cytotoxicity assay, against several syngeneic and allogeneic tumors. Very high reactivity was seen with effector cells from athymic nude mice, which was consistent with other evidence that the reactivity was not T‐cell dependent. Target cells susceptible to lysis included tumors induced by oncogenic type‐C viruses but also tumors induced by other means and expressing endogenous type‐C viruses. The levels of natural reactivity were influenced by age, with highest cytotoxicity produced by cells from 5‐ to 8‐week‐old mice. Lymph‐node cells, spleen cells, peritoneal exudate cells and peripheral blood lymphocytes all had cytotoxic reactivity. The specificity of the reactions was analyzed in detail by an inhibition assay. Evidence was obtained for natural reactivity against several different antigens, each apparently associated with expression of murine endogenous type‐C viruses.

The aim of our study was to quantify the risk of second malignant neoplasms (SMNs) among long‐term survivors of neuroblastoma and to study the influence of treatment on this risk. We studied data from 544 5‐year survival patients diagnosed with neuroblastoma before age 16 years at 8 French and British treatment centres from 1948 to 1986. After an average follow‐up of 15 years (range, 5–38 years), 12 children developed a total of 13 SMNs, whereas 1.19 were expected from general population rates. Among these SMNs, there were 5 thyroid and 3 breast cancers. Increases of the risks of SMN were observed with time since neuroblastoma diagnosis and attained age. In a multivariate analysis, the relative risk of SMN associated with radiotherapy was 4.3 (95% CI 0.8–78), whereas no increased risk of SMN was associated with the administration of chemotherapy as a whole (RR = 0.4, 95% CI 0.1–1.9). Young children treated for a neuroblastoma have significantly increased risks of SMN over 3 decades of follow‐up. Radiotherapy treatment was found to be an important risk factor for developing SMNs, whereas no effect of chemotherapy was evidenced. Although our findings reflect the late effects of past therapeutic modalities, they underscore the importance of long‐term surveillance of young children treated for a neuroblastoma. For these patients, many more years of follow‐up are required to appreciate their overall risks of treatment‐related SMNs. © 2003 Wiley‐Liss, Inc.