tumor cell biology program - Sylvester Comprehensive Cancer Center

eceptor tyrosine kinase ErbB2. The
mucin subunit ASGP-1 also has antiadhesive
activity. The human MUC4 has
corresponding transmembrane (MUC4
beta) and mucin (MUC4 alpha) subunits,
with similar growth factor domains
and anti-adhesive potential. These characteristics
suggest SMC/MUC4 play a
functional role in normal cells by providing
a direct protective barrier at the
cell surface to limit adsorption of microbes
and other noxious agents to the
epithelial surface, while also participating
in repair and cell replacement processes
in the epithelia as a ligand and
modulator of signalling via ErbB2.
Disregulation of these functions may lead
to transformation of the normal epithelia
to a neoplastic phenotype by means
of autocrine stimulation of cell growth
and proliferation via activation of ErbB2.
The antiadhesive properties of the
ASGP-1/ MUC4 alpha component of
the molecules result in reversible disruption
of integrin-mediated cell adhesion
to the extracellular matrix, and may be
important in the development of metastatic
potential of the transformed cell.
Over-expression or disregulation of the
ErbB2 oncoprotein and cell surface
integrins have both been implicated in
the initiation and progression of head
and neck cancers.
Immunocytochemical analyses have
shown that the oral cavity is one of the
earliest sites of expression of SMC during
development of the rat, and that the
molecule is expressed throughout the
upper aerodigestive tract and in the salivary
glands of the adult animal. This
study postulates that MUC4 is similarly
expressed in the epithelia of the human
upper aero-digestive tract and salivary
glands, and that the molecule participates
in the normal processes of cellular protection,
repair, and replacement of these
vulnerable tissues. It is further postulated
that alterations in MUC4 expression are
relevant to the cell biology of neoplastic
transformation and subsequent invasion
and metastasis of these cancers. The hypotheses
of this study are three-fold:
1) MUC4 expression is altered in head
and neck malignancies compared with
normal epithelial expression. 2) Cellular
expression of MUC4 modulates as lesions
progress from dysplastic
noninvasive lesions to invasive lesions
with regional and distant metastases. 3)
Characterization of MUC4 expression in
neoplasia will correlate with tumor behavior
such as invasion and metastasis,
and clinical outcomes such as likelihood
of recurrence and prognosis.
Preliminary data from immunoblotting
studies using fresh frozen operative
tissue samples and immunohistochemical
localization studies using
paraffin embedded tissue blocks have
identified MUC4 throughout the normal
human upper aerodigestive tract
mucosa, and in major and minor salivary
glands. MUC4 is identified in squamous
cell carcinomas of the upper
aerodigestive tract, as well as in metastatic
cervical lymph nodes. SMC/MUC4 is
also identified in a variety of salivary neoplasms.
Alterations in the normal mucosal
MUC4 expression are seen in
otherwise histologically normal mucosa
adjacent to invasive tumors. For squamous
cell carcinomas, a trend towards
decreased MUC4 staining in poorly differentiated
tumors is seen. Ongoing studies
seek to correlate MUC4 expression
with clinical outcomes for head and neck
squamous cell carcinoma and mucoepidermoid
carcinoma of major and minor
salivary glands. These studies may establish
MUC4 as a potential molecular
prognostic marker for these tumors. The
cell surface location of differentially expressed
or altered SMC/MUC4 as a potential
tumor marker may, in turn, offer
an important avenue for novel cancer
treatments for head and neck malignancies.
PUBLICATIONS
Weed, DT, Carraway, K, Carvajal,
M, Lee, T, Pacheco, J, Gomez-Fernandez,
C, Bello, A and Goodwin, WJ. MUC4
(sialomucin complex) expression in salivary
tumors and squamous cell carcinoma
of the upper aerodigestive tract.
Otolaryngology Head Neck Surgery
121:87, 1999.
Civantos, FJ, Roth, J, Goodwin, WJ
and Weed, DT. Sensory recovery in
myelolabial flaps used for oral cavity reconstruction.
Otolaryngology Head
Neck Surgery 122:509, 2000.
Li, P, Arango, ME, Perez, RE, Reis,
CA, Bonfante, EL, Weed, DT and
Carraway, KL. Expression and localization
of immunoreactive-sialomucin complex
(Muc4) in salivary glands. Tissue
and Cell 33:111, 2001.
Catherine F. Welsh, M.D.
Assistant Professor of Medicine
DESCRIPTION OF RESEARCH
Dr. Welsh is studying cell cycle progression
through the G1 phase and
its regulation by growth factor receptors
and adhesion to the extracellular matrix.
She is particularly interested in how these
signaling pathways contribute to breast
cancer tumorigenesis and progression.
Signals from the plasma membrane emanating
from receptor tyrosine kinases as
well as integrins are each required for
G1 progression. Cell spreading and
cytoskeletal integrity as a consequence of
integrin engagement are also necessary.
Studies involve the role of Rho family
GTPases, a subset of the Ras superfamily,
in the regulation of adhesion-dependent
cell cycle progression. These proteins
have been shown to play a role in
integrin- and growth factor-mediated signaling,
and they are potent mediators of
cytoskeletal architecture during cell
spreading. Furthermore, they are situated
to play a key role in the regulation of
adhesion-dependent cell cycle progression.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2002