Presence Of Premalignant Lesions Research Articles

Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1–3 and Atypical Flat Lesions—AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.

Tabaquismo y cáncer de piel no melanoma

The incidence of non melanoma skin cancer, squamous cell carcinoma (SCC) y basal cell carcinoma (BCC) is constantly rising all over the world. Ultraviolet (UV) radiation exposure is an established environment risk for SCC and BCC, others risk factors such as skin type, age, chemical exposure and the presence of premalignant lesions within others risk factors have been well studied. The association of tobacco smoking with non melanoma skin cancer has been controversial and inconsistent. The objective of this article was to perform a systematic review of the published finding on the association between tobacco smoking and the presence of SCC and BCC. For this purpose, all reviews and meta-analysis studies, as well as some selected individual scientific research on the subject were analyzed. The individual scientific research included in this review were selected according scientific criteria parameters such as the number of patients studied. According to the results of this review, there is a strong association between tobacco smoking and SCC; however, this association is not that clear in BCC. We need to understand further the mechanisms behind the tobacco smoking and the development of SCC. In the future, more scientific research is needed in the subject.

Abstract 896: The airway field of injury reflects gene expression changes associated with the presence of lung squamous premalignant lesions

Abstract Lung squamous cell carcinoma (SCC) arises in the epithelial layer of the bronchial airways and is preceded by the development of premalignant lesions (PMLs). The molecular events involved in the progression of PMLs to lung SCC are not clearly understood as not all PMLs that develop go on to form carcinoma. In addition, the majority of lung cancer chemoprevention agents tested to date are ineffective. Molecular characterization of the airway field of injury in individuals with PMLs could provide novel insights into the earliest molecular events associated with carcinogenesis and identify biomarkers to guide lung cancer detection and chemoprevention. RNA-sequencing was conducted on cytologically normal airway brushings from current and former smokers with (n = 50) and without (n = 25) PMLs as part of the British Columbia Lung Health Study. Linear modeling strategies were used to identify 280 differentialy expressed genes at FDR<0.002 between subjects with and without PMLs. Pathway analysis using GSEA and ROAST revealed enrichment of genes involved in the electron transport chain and oxidative phosphorylation pathways in subjects with PMLs. These findings were validated by measuring the cellular bioenergetics of cultured epithelial cells from biopsies of PMLs and non-lesion areas. Baseline oxygen consumption rates were 2.5 fold higher (p<0.001) and the spare respiratory capacity was 1.5 fold higher (p<0.001) in PML cultures. These data suggest that metabolism-associated gene expression observed in the field of injury of PMLs is correlated with PMLs. In addition, there is a significant concordant enrichment (FDR<0.05) between the signature and gene expression in PMLs adjacent to SCC tumors, in SCC tumors, and in the field of individuals with lung cancer. This concordance led to the development of a 200-gene biomarker that accurately predicts the presence of PMLs (AUC = 0.90 n = 17 independent samples). Importantly, this biomarker was also predictive (AUC -.72) of progression/stability vs. regression of these premalignant lesions in an independent cohort of cytologically normal airway brushings collected as part of the RPCI screening clinic (n = 18). This is the first study to comprehensively profile gene expression changes in airway epithelial cells in the presence of PMLs. A subset of these changes reflects the earliest changes in the process of lung squamous cell carcinogenesis including the genes involved in cellular metabolism. However, the molecular alterations in the field of injury are dynamic as bronchial lesions either progress or regress these changes may be leveraged to monitor efficacy in chemoprevention trials. In addition monitoring molecular changes in high-risk smokers may identify smokers with PMLs that should receive lung cancer screening as well as lay the foundation for personalized lung cancer chemoprevention. Citation Format: Sarah A. Mazzilli, Ania Tassinari, Yaron Gethalter, Gang Lui, Mary Pine, Stephen Lam, Mary Reid, Suso Platero, Marc Lenburg, Avrum Spira, Jennifer Beane. The airway field of injury reflects gene expression changes associated with the presence of lung squamous premalignant lesions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 896.

Predictive values of vascular endothelial growth factor and microvessel-density levels in initial biopsy for prostate cancer

Angiogenesis is an important factor in the development and progression of prostate cancer (PCA). We aimed to investigate the values of vascular-endothelial-growth-factor (VEGF) expression level and microvessel density (MVD) in the prediction of PCA diagnosis at repeated prostate biopsy (re-PBx). We retrospectively evaluated 167 patients with re-PBx according to elevated prostate-specific antigen levels, suspicious digital rectal examination, and the presence of premalignant lesions. Patients with PCA on re-PBx were included in the cancer group (n = 17). Patients with benign prostatic hyperplasia or normal tissues on re-PBx were included in the control group (n = 21). The groups were compared according to the expression level of VEGF and MVD in initial prostate biopsy. There was no statistically significant difference between groups according to age and serum prostate-specific-antigen values. The mean VEGF scores of the cancer and control groups were 232.64 ± 11.14 and 183.09 ± 14.56, respectively (p < 0.05). The mean MVD of the biopsy samples in the cancer and control groups were 246.47 ± 17.59 n/mm2 and 197.33 ± 16.26 n/mm2, respectively (p < 0.05). The cutoff values of VEGF scores and MVD were set as 200 and 215, respectively, for PCA detection in our study. Our results showed that the expression level of VEGF and MVD significantly increased in the initial prostate-biopsy samples of patients with PCA diagnosed with re-PBx. The evaluation of VEGF expression level and MVD might have an important value in the prediction of PCA at re-PBx. The expression level of VEGF and MVD should be kept in mind as PCA-related histopathological changes that indicate the increased angiogenesis in prostatic tissue.

Chemoprevention of Squamous Cell Carcinoma of the Head and Neck: No Time to Lose Momentum

The prospects for chemoprevention to reduce the incidence of squamous cell carcinoma of the head and neck (SCCHN) are great. The tissue at risk for harboring disease is relatively accessible for examination and biopsy. Patients appropriate for study can be easily identified by their risk factors and the presence of premalignant lesions. Our understanding of the pathogenesis of SCCHN is ever increasing, and offers new opportunities to explore strategies for prevention therapies. In this issue of Cancer Prevention Research, Saba and colleagues report on a phase Ib trial of celecoxib plus erlotinib to prevent progression to higher-grade dysplasia or invasive carcinoma in patients with oral premalignant lesions. The overall response rate was 57%, though by the time of last analysis, 85% of patients relapsed. In this commentary, challenges to the success of chemoprevention clinical trials for SCCHN, such as pitfalls in using surrogate biomarkers and reversal of histologic premalignant changes as study endpoints, are discussed. In addition, strategies to help ensure further development in the field of head and neck cancer prevention are reviewed. These include focusing efforts on tobacco cessation and human papillomavirus vaccination, targeting key molecular drivers of head and neck carcinogenesis, and focusing on combination strategies that have the potential to eradicate premalignant clones, even if some toxicity is encountered.

Promoter Polymorphisms of ST3GAL4 and ST6GAL1 Genes and Associations with Risk of Premalignant and Malignant Lesions of the Cervix

Sialyltransferase gene expression is altered in several cancers, including examples in the cervix. Transcriptional regulation of the responsible genes depends on different promoters. We aimed to determine the association of single-nucleotide polymorphisms in the B3 promoter of the ST3GAL4 gene and the P1 promoter of the ST6GAL1 gene with cervical premalignant lesions or cervical cancer. A blood sample and/or cervical scrapes were obtained from 104 women with normal cytology, 154 with premalignant lesions and 100 with cervical cancer. We also included 119 blood samples of random donors. The polymorphisms were identified by sequencing from PCR products. For the B3 promoter, a fragment of 506 bp (from nucleotide -408 to +98) was analyzed, and for the P1 promoter a 490 bp (-326 to +164) fragment. The polymorphism analysis showed that at SNP rs10893506, genotypes CC and CT of the ST3GAL4 B3 promoter were associated with the presence of premalignant lesions (OR=2.89; 95%CI 1.72-4.85) and cervical cancer (OR=2.23; 95%CI 1.27-3.91). We detected only one allele of each polymorphism in the ST6GAL1 P1 promoter. We did not detect any genetic variability in the P1 promoter region in our study population. Our results suggest that the rs10893506 polymorphism -22C/T may increase susceptibility to premalignant and malignant lesions of the cervix.

Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis : Lippman SM, Benner SE. Waun Ki Hong Thoracic/Head/Neck Med. Oncol. Dept., Texas Univ. M. D. Anderson Can. Ctr., Box 80, 1515 Holcombe Boulevard, Houston, TX 77030. Cancer Res 1994; 54: Suppl 2025s-8s

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.