Development Of Squamous Cell Cancer Research Articles

Low-Dose Retinoids Effective for Chemoprophylaxis in Transplant Patients

Oral retinoids in high doses can suppress the development of squamous cell cancer (SCC), but adverse effects limit their long-term use. Organ transplant recipients have an increased risk for SCCs. In this retrospective, before-and-after study from England, 28 organ transplant recipients who had developed at least one SCC …

Propagation of human papillomavirus 16 using a novel adenovirus and cre/loxp mechanism

Problem: Human papillomavirus type 16 (HPV16) infection is a major risk factor for the development of squamous cell cancers of the cervix and of the head and neck. A major barrier to understanding the progression from initial infection to cancer has been the lack of in vitro models that allow infection, replication, and persistence of the viral genome as an episome in differentiated epithelial cells. Methods: To overcome this barrier, we designed an adenoviral delivery vector that contained a full HPV16 genome flanked by LoxP homologous recombination sites plus a fluorescent reporter that was expressed only after the HPV genome was excised by Cre recombinase. Results: This system delivered circular HPV16 genomes to cervical epithelial cells and well-differentiated human airway epithelia. Following delivery, the HPV16 genome replicated and persisted as an episome in cervical keratinocytes. These cells developed an immortalized phenotype and a dysplastic epithelial appearance. Moreover, induction of differentiation led to the expression of late genes and production of infectious HPV16 virions. Conclusion: This work provides a novel means of introducing biologically active HPV genomes into epithelial cells, which are normally difficult to transfect. These methods will allow the study of HPV genome replication and gene expression in the earliest stages of HPV genome establishment and may provide a means with which to study non-oncogenic HPV viral types. Significance: Understanding the papillomavirus life cycle may aid in developing novel treatments for HPV-related head and neck diseases. Support: None reported.

Propagation of infectious human papillomavirus type 16 by using an adenovirus and Cre/LoxP mechanism.

Human papillomavirus type 16 (HPV16) infection is a major risk factor for the development of squamous cell cancers of the cervix and of the head and neck. A major barrier to understanding the progression from initial infection to cancer has been the lack of in vitro models that allow infection, replication, and persistence of the viral genome as an episome in differentiated epithelial cells. To overcome this barrier, we designed an adenoviral delivery vector that contained a full HPV16 genome flanked by LoxP homologous recombination sites and a fluorescent reporter that was expressed only after the HPV genome was excised by Cre recombinase. This system delivered circular HPV16 genomes to cervical epithelial cells and well differentiated human airway epithelia. After delivery, the HPV16 genome replicated and persisted as an episome in cervical keratinocytes. These cells developed an immortalized phenotype and a dysplastic epithelial appearance. Moreover, induction of differentiation led to the expression of late genes and production of infectious HPV16 virions. This work provides a means of introducing biologically active HPV genomes into epithelial cells, which are normally difficult to transfect. These methods allow the study of HPV genome replication and gene expression in the earliest stages of HPV genome establishment, and they may provide a means to study nononcogenic HPV viral types.

Down-regulation of members of glycolipid-enriched membrane raft gene family, MAL and BENE, in cervical squamous cell cancers.

Persistent human papillomavirus infections cause infected epithelial cells to lose cellular polarity leading to cell transformation. Glycolipid-enriched membrane (GEM) rafts are implicated in polarized sorting of apical membrane proteins in epithelial cells and even in signal transduction. The MAL and BENE are essential component of the GEM raft's machinery for apical sorting of membrane proteins. In this study we demonstrated down-regulation of MAL and BENE mRNA in over two-thirds of primary cervical squamous cell cancers (14 and 15 of 20 cases, for MAL and BENE, respectively) when compared to corresponding non-cancerous uterine squamous cells. Allelic loss or hyper-methylation was not accompanied by MAL or BENE mRNA down-expression in human primary cervical cancers in microsatellite allelic analysis and HpaII-PCR-based methylation analysis of the MAL and BENE genomic region. In addition, we note down-regulation of these genes in established cervical cancer cell lines. These results suggest that down-regulation of MAL and BENE genes, which are essential components of the cellular polarized sorting system, play an important role in human cervical squamous cell cancer development.

Multiple suspicious lesions detected by autofluorescence bronchoscopy predict malignant development in the bronchial mucosa in high risk patients

Autofluorescence bronchoscopy (AFB) has been shown to be sensitive to detect preneoplastic lesions in central airways. Apart from bronchial mucosa thickness, tissue autofluorescence is also related to the biochemical properties of the target cells. Genetic studies have shown molecular abnormalities to be present in histologically normal mucosal specimens. Forty-six high-risk individuals, free of micro-invasive cancer at the initiation of the study, were included in this analysis and have been subjected to repeat bronchoscopic examinations every 4–6 months. They had previous curatively treated lung cancer ( n=18), ENT tumor ( n=11) or were at risk to acquire lung cancer primaries ( n=17). Baseline AFB is scored for each suspicious lesion, thus the total score represents the number of AFB suspicious lesions present in each individual at risk. Baseline AFB score was correlated to outcome, i.e. the development of squamous-cell cancer (SCC) in each individual. So far, 11/46 (24%) of the individuals acquired SCC. Follow up has been 12–80 months. All five individuals with ≥3 lesions (100%, 12–36 months), five of the ten (50%, 12–48 months) individuals who had two lesions and one among the 12 (8%, 36 months) individuals with one suspicious AFB lesion, developed SCC. Up till now (12–80 months), the remaining 19 individuals without any suspicious AFB lesion have not acquired SCC. The average AFB score for the group of individuals which developed SCC was significantly different ( P<0.001) from the remaining individuals who did not acquire SCC (2.64±1.1 vs. 0.6±0.7 S.D.). The number of suspicious lesions at baseline AFB is a good predictor for the development of SCC in the individuals at risk in our study population. This finding is compatible with field carcinogenesis and warrants a more upfront use of AFB in a lung cancer screening to sift the different risk-cohorts in a population mainly at risk for developing metachronous lung cancer.

The expression of fatty acid synthase (FASE) is an early event in the development and progression of squamous cell carcinoma of the lung

Correlation of elevated levels of the lipogenic enzyme, fatty acid synthase (FASE), with advanced stages of some cancers has drawn attention to this enzyme as a possible marker of poor prognosis. Because recent studies have shown that cancer cells are dependent on fatty acid synthetic activity and pharmacologic inhibitors of this enzyme are selectively cytotoxic to cancer cells, expression of FASE also may provide a potential target for intervention in the neoplastic process. To determine the potential usefulness of expression of FASE in the neoplastic process of the lung, we evaluated its pattern of expression immunohistochemically in archival specimens from 60 human lung specimens with squamous cell cancer (SCC) and associated “preneoplastic” lesions compared with its expression in the normal bronchial epithelium of 60 noncancer specimens. The expression of FASE was significantly higher in SCC associated uninvolved bronchial epithelium (mean = 0.40 ± 0.03, median = 0.38) compared with its expression in the bronchial epithelium of noncancer specimens (mean = 0.18 ± 0.02, median = 0.16) indicating its early expression. We also observed a statistically significant step-wise increase in FASE expression from SCC associated uninvolved bronchial epithelium (mean = 0.40 ± 0.03, median = 0.38) to epithelial hyperplasia (0.58 ± 0.04, median = 0.57) to SCC (1.53 ± 0.06, median = 1.50). The results suggested that expression of FASE is an early event in the development and progression of SCC of the lung. The inhibition of fatty acid synthesis by inhibiting enzymatic function with metabolic analogues may be a useful strategy in the treatment of SCCs. The expression of FASE in early lesions such as SCC associated uninvolved bronchial epithelium and epithelial hyperplasia might also provide a potential means for intervention early in the neoplastic process in the lung or even preventing their malignant transformation to invasive carcinomas. H UM P ATHOL 31:1068-1073.

Prostaglandin-H-synthase isozyme expression in normal and neoplastic human skin.

Expression of prostaglandin-H-synthase (PGHS) isozymes was analyzed in 50 biopsies of normal human skin and of pre-malignant and malignant skin lesions, by means of quantitative RT-PCR, immunoprecipitation and Western blotting, as well as immunohistochemistry. Normal skin constitutively expressed PGHS-1 in all cell layers of the epidermis, in endothelial cells of small blood vessels and in sweat-gland epithelium. PGHS-2 expression was very low and restricted to a few keratinocytes of the interfollicular and follicular epidermis. Steady-state concentrations of PGHS-1 and PGHS-2 mRNA were similar in normal skin and in basal-cell carcinomas, but PGHS-1 mRNA was reduced and PGHS-2 mRNA was elevated in actinic keratoses, squamous-cell carcinomas and keratoacanthomas. PGHS-1 protein was detected in all tumor biopsies, being occasionally increased in basal-cell carcinomas. High amounts of PGHS-2 protein were found in actinic keratoses, squamous-cell carcinomas and keratoacanthomas, but not in basal-cell carcinomas. Four malignant melanomas included in this study contained PGHS-1 but no PGHS-2 protein. Immunohistochemical analysis of the biopsies identified keratinocytes, in addition to cells of inflammatory infiltrates and of dendritic morphology, as the major PGHS-expressing cell types. PGHS-2-specific signals were spread throughout the epidermal part of actinic keratoses and squamous-cell carcinomas. These data suggest that constitutive up-regulation of PGHS-2 expression is a consistent pre-malignant event in squamous-cell cancer development in man, as it is in animal models of skin carcinogenesis. Thus, pre-cancerous lesions such as actinic keratoses present a likely target for chemoprevention of skin cancer by selective PGHS-2 inhibitors.

Prostaglandin‐H‐synthase isozyme expression in normal and neoplastic human skin

Expression of prostaglandin-H-synthase (PGHS) isozymes was analyzed in 50 biopsies of normal human skin and of pre-malignant and malignant skin lesions, by means of quantitative RT-PCR, immunoprecipitation and Western blotting, as well as immunohistochemistry. Normal skin constitutively expressed PGHS-1 in all cell layers of the epidermis, in endothelial cells of small blood vessels and in sweat-gland epithelium. PGHS-2 expression was very low and restricted to a few keratinocytes of the interfollicular and follicular epidermis. Steady-state concentrations of PGHS-1 and PGHS-2 mRNA were similar in normal skin and in basal-cell carcinomas, but PGHS-1 mRNA was reduced and PGHS-2 mRNA was elevated in actinic keratoses, squamous-cell carcinomas and keratoacanthomas. PGHS-1 protein was detected in all tumor biopsies, being occasionally increased in basal-cell carcinomas. High amounts of PGHS-2 protein were found in actinic keratoses, squamous-cell carcinomas and keratoacanthomas, but not in basal-cell carcinomas. Four malignant melanomas included in this study contained PGHS-1 but no PGHS-2 protein. Immunohistochemical analysis of the biopsies identified keratinocytes, in addition to cells of inflammatory infiltrates and of dendritic morphology, as the major PGHS-expressing cell types. PGHS-2-specific signals were spread throughout the epidermal part of actinic keratoses and squamous-cell carcinomas. These data suggest that constitutive up-regulation of PGHS-2 expression is a consistent pre-malignant event in squamous-cell cancer development in man, as it is in animal models of skin carcinogenesis. Thus, pre-cancerous lesions such as actinic keratoses present a likely target for chemoprevention of skin cancer by selective PGHS-2 inhibitors. Int. J. Cancer 82:648–656, 1999. © 1999 Wiley-Liss, Inc.

Loss of 18q predicts poor survival of patients with squamous cell carcinoma of the head and neck.

Tumor suppressor genes play an important role in normal growth regulation. Loss or inactivation of these genes has been implicated in the development of squamous cell cancer and progression of neoplasia. Previous studies in our laboratories have implicated chromosome 18 long-arm deletions as a possible marker of progression in head and neck squamous cell cancer (HNSCC). To test this hypothesis, we evaluated DNA from 67 HNSCC patients for loss of heterozygosity (LOH) at 18q loci, and for association of LOH with survival. Tumor and normal DNA were extracted from fresh tissue and paraffin blocks and were amplified by PCR using primers for three microsatellite repeat polymorphisms in 18q (D18S336, D18S34, and MBP). A total of 27 (40%) patients had LOH of 18q, and these patients had a statistically significantly poorer two-year survival compared to those without 18q LOH (30% vs. 63%; P = 0.008). In a Cox proportional hazards model in which time from diagnosis to death was the outcome variable, patients with 18q LOH had an unadjusted relative risk (RR) of death of 2.46 (P = 0.005). When 18q LOH was placed in a multivariate model controlling for possible confounders in the study, the RR for death was still elevated (RR = 2.10; P = 0.025). The observation of a prognostic association between 18q LOH and poor patient survival suggests that loss of an 18q tumor suppressor gene or genes is important in the progression of HNSCC.

Cutaneous T-cell lymphoma: value of CT in staging and determining prognosis.

The usefulness of CT in diagnosing, staging, and establishing the prognosis in cutaneous T-cell lymphoma was assessed. CT abnormalities indicative of the disease, diffuse peripheral adenopathy and skin lesions, as well as less specific signs of generalized lymphoma, were correlated with clinical findings. The study group comprised 33 patients from a total of 87 with pathologically proved cutaneous T-cell lymphoma who were seen at the University of Pittsburgh Medical Center between 1986 and 1991 and who had CT scans. All patients had body CT imaging with contiguous axial sections no thicker than 10 mm of the chest, abdomen, and pelvis; other CT studies were performed as clinically indicated. Because of the cutaneous nature of this lymphoma, collimation included the skin surface. In 10 of the 33 patients, all of whom had stage II or higher disease, abnormalities indicative of cutaneous T-cell lymphoma were seen on CT scans. All 10 had multiple areas of focal skin thickening or plaques several centimeters or more in diameter and 5 mm or greater in thickness affecting the dermal tissues while leaving the subcutaneous fat intact. Extension of individual lesions below the dermis was associated with the development of squamous cell cancers in two patients, both of whom had previous topical therapy. Seven of the 10 also had an unusual pattern of lymphadenopathy: the mediastinum or paraaortic regions were spared while enlarged peripheral nodes were seen in both the axillary and inguinal areas. Skin abnormalities were seen on CT scans of all patients with lymphadenopathy. CT findings in cutaneous T-cell lymphoma are related to the pathophysiology of the disease: cutaneous plaques and diffuse peripheral adenopathy that spare the mediastinal and paraaortic lymph nodes. Although the skin lesions can be easily evaluated clinically, secondary malignant neoplasms arising in treated skin lesions can be found with CT by their extension into the subcutaneous fat.

Human papilloma virus type 16 periungual carcinoma

To the Editor.— The article by Moy et al1reveals a number of risk factors for the development of squamous cell cancer of the nailbed. It was known already that at cutaneous nongenital sites, human papillomavirus (HPV) 5 produced "epidermodysplasia verucci formis" with invasive malignant features. Moy et al now report the presence of HPV 16 in six of nine patients with periungual squamous cell carcinoma. Human papillomavirus 16 has been identified previously as a cause of condylomata acuminata. Human papillomaviruses 6,11,16, and 18 have been found in the lesions of this sexually transmitted disease.2,3When found in children, these children receive close medical supervision for the development of cervical and vulvar dysplasia and cancer. Also, children with genital warts of these types generally are referred for investigation of possible child sexual abuse. We therefore are concerned about the finding of HPV 16 lesions in a nongenital site.

Human Papillomavirus Type 16 Periungual Carcinoma

To the Editor.— The article by Moy et al1reveals a number of risk factors for the development of squamous cell cancer of the nailbed. It was known already that at cutaneous nongenital sites, human papillomavirus (HPV) 5 produced epidermodysplasia verucci formis with invasive malignant features. Moy et al now report the presence of HPV 16 in six of nine patients with periungual squamous cell carcinoma. Human papillomavirus 16 has been identified previously as a cause of condylomata acuminata. Human papillomaviruses 6,11,16, and 18 have been found in the lesions of this sexually transmitted disease.2,3When found in children, these children receive close medical supervision for the development of cervical and vulvar dysplasia and cancer. Also, children with genital warts of these types generally are referred for investigation of possible child sexual abuse. We therefore are concerned about the finding of HPV 16 lesions in a nongenital site.