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Gene Therapy for Lung Cancer
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Choon Taek Lee, David P. Carbone
Lung cancer is not an easy target for gene therapeutic approaches because it appears to be poorly immunogenic and often metastatic. Many genetic abnormalities have been found in lung cancer, however, and there are thus many potential targets for directed gene therapy approaches. Lung cancer also has the advantage of having a well-defined environmental etiology and discernible and accessible preneoplastic lesions. These preneoplastic lesions may ultimately be the most promising gene therapeutic targets.
General Biological Aspects of Oncogenesis
Published in Pimentel Enrique, Oncogenes, 2020
The term ‘‘precancerous’’ was coined by the end of the last century for some epidermal changes showing increased liability to subsequent malignant transformation.76 During the preneoplastic stage normal cells, or cells which are apparently normal, undergo changes that determine in them a predisposition or an enhanced possibility to be transformed into cells with a clear malignant behavior. However, under natural conditions most cells from preneoplastic lesions are either destroyed or may revert to normalcy. In fact, only a small fraction of the cells from preneoplastic lesions, or a minority of preneoplastic lesions in general, will give rise to malignant tumors, and processes of “redifferentiation” or “remodeling” may regularly occur within populations of preneoplastic cells.77
Urinary System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Kendall S. Frazier, John Curtis Seely
The cells of the parietal epithelium of Bowman’s capsule are typically lined by thin squamous epithelium, but tall cuboidal epithelium may be present in mice and rats depending on the strain. These cells are under hormonal influence in mature male mice and changes in circulating levels of testosterone may affect their morphology. Drugs or agents which affect the androgenic pathways have the potential to induce this lesion, which involves both an increase in cell number as well as changes in morphology. Metaplasia of Bowman’s capsule may occur in female mice and a similar change to cuboidal epithelium occurs in older rats, more commonly in males (Hard et al. 1999). Parietal epithelium may also undergo hyperplasia with advanced glomerular disease, particularly in rat CPN or severe glomerulonephritis, and has been reported commonly in SHRs (Peter et al. 1986). The lesion does not occur in monkeys, minipigs, or dogs. This change needs to be differentiated from fixation artifact resulting from extrusion of proximal tubular epithelium into the capsular space, where the epithelium not only resembles but also is indistinguishable from PCT epithelium. It is not associated with any organ weight or clinicopathologic alterations. These metaplastic/hyperplastic changes are not considered to be preneoplastic lesions, and the clinical relevance to humans is probably negligible other than the hormonal implications.
Folic Acid Modulates DMBA/TPA–Induced Changes in Skin of Mice: A Study Relevant to Carcinogenesis
Published in Journal of Dietary Supplements, 2018
Ashwani Koul, Navneet Kaur, Neha Arora Chugh
Folate insufficiency in normal epithelial tissues appears to enhance the risk of developing neoplastic characteristics (Kim, 2006). Modest doses of FA taken before the occurrence of preneoplastic lesions could suppress the development of cancer in normal tissues, whereas high doses taken after the establishment of preneoplastic lesions could potentiate cancer development and progression (Kim, 2006; Ulrich and Potter, 2006). Folate supplementation can enhance the stability of DNA methylation before tumorigenesis, playing a preventive role against tumor, but after insidious lesions occur, it can promote the development of cancers by benefiting the proliferation of tumor cells. It is thus relatable that high folate status promotes tumor progression, which suggests that folate might play dual roles depending on the dosage and timing of the exposure. Although in the present study a moderate level of folate supplementation (four times the basal dietary requirements) mitigated DMBA/TPA-induced carcinogenic alterations, keeping in mind the time-dependent effect of folate on carcinogenesis, additional research is required to fully understand the role of supplemental dietary folate/FA in skin carcinogenesis.
OX40 triggering concomitant to IL12-engineered cell vaccine hampers the immunoprevention of HER2/neu-driven mammary carcinogenesis
Published in OncoImmunology, 2018
Patrizia Nanni, Carla De Giovanni, Alessia Burocchi, Giordano Nicoletti, Lorena Landuzzi, Arianna Palladini, Marianna Lucia Ianzano, Ivano Arioli, Mario P. Colombo, Pier-Luigi Lollini
In our study, combined immunotherapy was investigated to prevent the progression of a HER2/neu-driven spontaneous carcinogenic program. It was started when only preneoplastic lesions were present and lasted for several months during which tumor growth was delayed but progressed anyway. This implies that mice had already been exposed to tumor antigen, i.e. even the pretreatment with aOX40 did not find truly naïve mice. Several models studied so far administered aOX40 to truly naïve mice and then vaccinated them or challenged them with tumor cells. Patients are much more similar to our model (not truly naïve) than to vaccination-challenge model systems. Furthermore prevention studies span several months, during which the immune response is edited by tumor growth, and the microenvironment is continuously changing, because studies last up to one year and a half. Treg frequency increases with age28 and strong age-related differences in responses induced by OX40 triggering have been reported.29 In a comprehensive immunological perspective, it should be kept in mind that our vaccine was adjuvanted by transduced expression of IL12 and by allogeneic histocompatibility antigens, therefore the observed effects are due to the combined activity of all the immune stimuli. Finally, HER2/neu driven mammary carcinogenesis ultimately affect all the mammary glands and, within each gland, multifocal neoplasms can arise. This is the reason why we choose a systemic administration route. Better results were obtained with the intratumoral administration of aOX40, however it is a route that could be hardly applied to a disseminated neoplasm.12
Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival
Published in OncoImmunology, 2021
Jebrane Bouaoud, Jean-Philippe Foy, Antonin Tortereau, Lucas Michon, Vincent Lavergne, Nicolas Gadot, Sandrine Boyault, Julie Valantin, Geneviève De Souza, Philippe Zrounba, Chloé Bertolus, Nathalie Bendriss-Vermare, Pierre Saintigny
A total of three control mice and nine mice treated by 4-NQO and sacrificed at different ages were included (Supplementary Figure S1 and S2). The histological mapping of 270 FFPE-tongues H&E sections from the nine 4-NQO treated mice showed an increasing incidence of histological lesions (i.e., Hyperplasia (H), Dysplasia (D), and Tumor (T)) over time (Figure 1). Preneoplastic lesions (H and D) were more common during the first 24 weeks. At week 28, histological lesions were observed in 97% of the sections analyzed. At week 32, T were observed in 72% of the sections analyzed.