Histopathologic and Immunohistochemical Reappraisal of DMBA-Induced Mammary Tumors Revealing a Potential Model for Cancer Stem Cell Pathophysiological and Pharmacological Studies
Philipi C De Souza, Laura F Rezende, Valeria B De Souza, Andre L Renno, Cristielle P Freitas, Marina Pavanello, Gilberto C Franchi, Jr, Alexandre E Nowill, Natalia GM Schenka, Rafael M Rocha, Glauce A Pinto, Fernando A Soares, Jose Vassallo, Andre A Schenka. UNICAMP, Campinas, SP, Brazil; UNIFAE, Sao Joao Da Boa Vista, SP, Brazil; Hospital A. C. Camargo, Sao Paulo, Brazil
Background: Dimetil-benz(a)anthracene (DMBA) is one of the most widely used carcinogenic agents. When given to Sprague-Dawley female rats, DMBA achieves great efficiency (>95%) and specificity for breast cancer induction. Paradoxically, histological reports of DMBA-tumors are scarse, too concise, and do not establish consistent parallels with human breast cancer, greatly impairing the application of model. Herein, for the first time, we provide a reclassification of DMBA-induced lesions according to the latest WHO criteria (2003) and investigate the expression of cancer stem cell (CSC) markers; since currently CSCs are major therapeutical targets.
Design: Twenty DMBA-induced breast neoplasms were independently assessed by two pathologists (one of them with veterinarian background) for (1) histologic type, (2) histologic grading (the Nottingham system, 1991), necrosis mapping and immunoexpression of typical CSC markers (CD34, CD133, CD117, CK14, Oct4, EpCAM, EGFR and p63).
Results: Most tumors was composed by more than one histologic type (12/20 cases); the most frequent histologic component was the ductal type, being present in 16/20 cases. Furthermore, in 15 of such cases, the ductal component was graded as well differentiated (final histologic grade 3-5). Other histologic variants: papillary carcinoma (10/20), phyllodes tumor (6/20), myoepithelial/metaplastic carcinoma (3/20) and lobular carcinoma (1/20). The average percentage of spontaneous necrosis was estimated at 14%. All neoplasms expressed at least two CSC markers, the most frequent being p63 and CK14 (>90% of cases). The frequency of positive cells within each tumor ranged from 17-46%.
Conclusions: The present model seems to favor the development of the ductal phenotype – the most common histologic type among human malignant neoplasia. The great histologic heterogeneity, both intra- and inter-tumors, the ability to form rare histologic variants, biphasic neoplasms, the clear signs of myoepithelial/basal differentiation and the consistent expression of CSC markers strongly suggest the participation of cancer stem cells in the development, progression and survival of these tumors. Altogether, the above findings support the great potentiality of this protocol of chemically induced carcinogenesis as a model for pathophysiological and pharmacological studies focused on the cancer stem cell hypothesis.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 279, Wednesday Morning