2 research outputs found
DNA vaccines against ErbB2+ Carcinomas: From mice to humans.
DNA vaccination exploits a relatively simple and flexible technique to generate
an immune response against microbial and tumor-associated antigens (TAAs). Its
effectiveness is enhanced by the application of an electrical shock in the area of plasmid
injection (electroporation). In our studies we exploited a sophisticated electroporation
device approved for clinical use (Cliniporator, IGEA, Carpi, Italy). As the target antigen is
an additional factor that dramatically modulates the efficacy of a vaccine, we selected
ErbB2 receptor as a target since it is an ideal oncoantigen. It is overexpressed on the cell
membrane by several carcinomas for which it plays an essential role in driving their
progression. Most oncoantigens are self-tolerated molecules. To circumvent immune
tolerance we generated two plasmids (RHuT and HuRT) coding for chimeric rat/human
ErbB2 proteins. Their immunogenicity was compared in wild type mice naturally tolerant
for mouse ErbB2, and in transgenic mice that are also tolerant for rat or human ErbB2. In
several of these mice, RHuT and HuRT elicited a stronger anti-tumor response than
plasmids coding for fully human or fully rat ErbB2. The ability of heterologous moiety to
blunt immune tolerance could be exploited to elicit a significant immune response in patients. A clinical trial to delay the recurrence of ErbB2+ carcinomas of the oral cavity,
oropharynx and hypopharynx is awaiting the approval of the Italian authorities
p130Cas is an essential transducer element in ErbB2 transformation
The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A.B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers.-Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. P., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. p130Cas is an essential transducer element in ErbB2 transformation