Preliminary studies on chemically-induced mouse skin tumors have shown that during tumor progression of squamous cell carcinomas (SCC), a variant poorly-differentiated neoplasm, called spindle cell carcinoma (SPCC), can arise that is characterized by enhanced invasiveness and metastatic potential. We have developed cell lines that correspond to the SCC and SPCC components of the same biphasic (SCC/SPCC) primary mouse tumor, in order to identify by differential display genes that intervene in the switch from SCC to SPCC. In particular, we focused on the absence of expression of a gene homologous to the human and rat PACE4 in the SCC cell line and its overexpression in the matched SPCC cell line. Since PACE4 is one of the several protein processing enzymes known as proprotein convertases (PCs), some of which have putative roles in activating substrates that are essential for cancer development, in this application we propose to investigate the function of PCs in tumor progression. The central hypothesis to be tested is that PACE4 and another PC, furin by activating specific targets such as matrix metalloproteinases (MMPs) enhance the invasiveness of SCC cells, thus constituting important components of the chain of events leading to an advanced malignant phenotype, culminating in the SPCC. In order to achieve this objective, we plan to: 1) investigate whether PACE4 expression is a significant feature of mouse tumors induced by protocols of chemical carcinogenesis and whether this expression is closely related to enhanced invasive/metastatic behavior and/or loss of differentiation; 2) determine whether furin participates in the process of tumor progression; 3) investigate the effect of exogenous expression of PC cDNAs on the acquisition of the invasive/metastatic phenotype of papilloma and low grade non-metastatic SCC cell lines; 4) investigate the role of PCs in the activation of MMPs in culture systems as well as in primary tumors; 5) determine the probable translational value of these findings by investigating the role of PCs in human SCCs and 6) initiate studies on the cause of PC upregulation by cloning and sequencing the PACE4 promoter region and create promoter-reporter transgenic mice to evaluate gene regulation in normal tissues and induced SCCs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075028-03
Application #
6342038
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
1999-01-13
Project End
2002-12-31
Budget Start
2001-01-05
Budget End
2001-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$302,552
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Bassi, Daniel E; Cenna, Jonathan; Zhang, Jirong et al. (2015) Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6). Mol Carcinog 54:1122-31
Bassi, Daniel E; Zhang, Jirong; Cenna, Jonathan et al. (2010) Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis. Neoplasia 12:516-26
Page, Robert E; Klein-Szanto, Andres J P; Litwin, Samuel et al. (2007) Increased expression of the pro-protein convertase furin predicts decreased survival in ovarian cancer. Cell Oncol 29:289-99
de Cicco, Ricardo Lopez; Bassi, Daniel E; Benavides, Fernando et al. (2007) Inhibition of proprotein convertases: approaches to block squamous carcinoma development and progression. Mol Carcinog 46:654-9
Lopez de Cicco, Ricardo; Bassi, Daniel E; Zucker, Stanley et al. (2005) Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. Cancer Res 65:4162-71
Bassi, Daniel E; Fu, Jian; Lopez de Cicco, Ricardo et al. (2005) Proprotein convertases: ""master switches"" in the regulation of tumor growth and progression. Mol Carcinog 44:151-61
Bassi, Daniel E; Lopez De Cicco, Ricardo; Cenna, Jonathan et al. (2005) PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression. Cancer Res 65:7310-9
Lopez de Cicco, Ricardo; Watson, James C; Bassi, Daniel E et al. (2004) Simultaneous expression of furin and vascular endothelial growth factor in human oral tongue squamous cell carcinoma progression. Clin Cancer Res 10:4480-8
Bassi, Daniel E; Mahloogi, Haleh; Lopez De Cicco, Ricardo et al. (2003) Increased furin activity enhances the malignant phenotype of human head and neck cancer cells. Am J Pathol 162:439-47
Mercapide, Javier; Lopez De Cicco, Ricardo; Castresana, Javier S et al. (2003) Stromelysin-1/matrix metalloproteinase-3 (MMP-3) expression accounts for invasive properties of human astrocytoma cell lines. Int J Cancer 106:676-82

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