SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R I M M U N O L O G Y P R O G R A M
EMSA, using probes specific for the IL-12p40
and iNOS murine promoters, revealed that in
macrophages from tumor-bearing mice, the binding
activities of NFκB and C/EBP are downregulated
in both promoters. Their results suggest
that in macrophages from tumor hosts, the
NFκB and C/EBP might be functionally impaired.
These two transcription factors are crucial
for appropriate innate immunity functions. Pertinent
studies are ongoing in Dr. Lopez’s laboratory
to determine if these deficiencies in the presence
of the tumor environment could be due to insufficient
amounts, inadequate levels of phosphorylation,
or impaired translocation of these
transcription factors.
Implantation of DA-3 mammary tumor
cells into BALB/c mice results in tumor growth,
metastatic lesions, and death. These cells were
transfected with genes encoding for either
the transmembrane (DA-3/TM) or secreted
(DA-3/sec) form of human mucin 1 (MUC1).
Although the gene for the secreted form lacks the
transmembrane and cytoplasmic domains, the 5’
sequences of these mucins are identical. However,
the gene for the secreted mucin isoform ends
with a sequence encoding for a unique 11 amino
acid peptide. The DA-3/TM cells or DA-3 cells
transfected with the neomycin vector only (DA-
3/neo) have the same in vivo growth characteristics
as the parent cell line. In contrast, DA-3/sec
cells implanted in nude mice resulted in tumor
development verifying the tumorigenic potential
of these cells. Pre-exposure of BALB/c mice to
DA-3/sec cells afforded protection against challenge
with DA-3/TM or DA-3/neo mammary
tumors and the unrelated tumors K7, an osteosarcoma,
and RENCA, a renal cell carcinoma.
Partial protection against subsequent tumor
challenges was also achieved by substituting
the 11 amino acid peptide found only in the
secreted mucin-1 isoform, as it also retarded the
growth of Lewis lung carcinoma cells in C57
BL/6 mice. These findings reveal that a unique
peptide present in the secreted MUC1 has
immunoenhancing properties and may be a
potential agent for use in immunotherapy.
SELECTED PUBLICATIONS
2002
Sun, QL, Charyulu, V, Lobo, D, and Lopez,
DM. Role of thymic stromal cell dysfunction in
the thymic involution of mammary tumor-bearing
mice. Anticancer Research 22:91-6, 2002.
Lopez, DM, Charyulu, V, and Adkins, B. Influence
of breast cancer on thymic function in mice.
Journal of Mammary Gland Biology and Neoplasia
7:191-99, 2002.
2003
Torroella-Kouri, M, Keith, JC, Ivanova, M, and
Lopez, DM. IL-11-induced reduction of C/EBP
transcription factor binding may contribute to
the IL-12 downregulation in tumor-bearing mice.
International Journal of Oncology 22:439-48,
2003.
Owen, JL, Iragavarapu-Charyulu, V, Gunja-
Smith, Z, Herbert, LM, Grosso, JF, and Lopez,
DM. Up-regulation of matrix metalloproteinase-
9 in T lymphocytes of mammary tumor bearers:
role of vascular endothelial growth factor. Journal
of Immunology 171(8):4340-51, 2003.
Torroella-Kouri, M and Lopez, D. Mammary
tumor derived TGF-β impairs crucial innate immune
responses in tumor hosts. Journal of Immunology
and Immunopathology 5:31-38, 2003.
HIGHLIGHTS/DISCOVERIES
• The thymus is crucial for the development of
T lymphocytes involved in cell-mediated immunity
to tumors. The thymuses of mammary
tumor bearers are profoundly involuted and
their studies have shown that this is not due to
a decrease of the thymocytes proliferation. A
minor increase of apoptosis was noted; however,
the major cause of this phenomenon appears to
be an arrest at an early stage of differentiation
possibly brought about by the direct or indirect
effects of tumor derived factors.
• A unique peptide with immunoenhancing
properties has been identified in a secreted form
of human MUC1 and used in vaccination ex-
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 115