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News and Publications
Cell Migration in Cancer Invasion
V. Quaranta, M. Bilban, E. Hintermann, N. Koshikawa, F. Ronca,
S. Schenk, M. Shang, A. Sharabi, N. Yang, D. Richards*
* University of California, San Francisco, CA
We focus on cancer invasion and metastasis, characteristics that
make cancer a life-threatening disease by severely limiting treatment
options such as surgical resection. It is unclear what triggers
invasion by tumor cells. We concentrate on epigenetic mechanisms
initiated by cues in the microenvironment of nests of cancer cells.
Examination of the cancer microenvironment is useful for dissecting
invasive mechanisms, because it is becoming increasingly clear that
tumors should be viewed as tissues whose organization may determine
whether or not invasion occurs. Understanding and manipulating the
tumor microenvironment may become a way to block invasion and metastasis.
Most human cancers arise from epithelia (e.g., breast, lung, colorectal,
bladder, prostate, and pancreatic cancers). A critical component
of the epithelial cell microenvironment is the basement membrane,
which is rich in laminin-5, a macromolecule in the extracellular
matrix. In most of our current studies, we are concentrating on
the interaction of laminin-5 with integrin-type receptors and matrix
metalloproteinases (MMPs), namely MT1-MMP and MMP2.
INTEGRINS AND MIGRATION OF LAMININ-5
Laminin-5 is exquisitely localized in the basement membrane, to
which epithelial cells adhere, forming continuous sheets. Mutations
in laminin-5 may result in blistering (e.g., in the epidermis or
the oral and esophageal mucosa), with severe health consequences.
Receptors for laminin-5 include 2 integrins, a3b1
and a6b4, which implement
migration and anchoring, respectively. Our working model is that
migration and anchoring must be coordinated to avoid conflicts.
In accordance, we found that substrate-stimulated migration (haptotaxis)
on laminin-5 strictly requires activation of a3b1
and is directly inhibited by engagement of a6b4
with ligand. Intracellular pathways that carry out this interference
include Her2/erbB2 and phosphatidylinositol-3´-kinase signaling.
We postulate that a breakdown in this interference may play a role
in cancer invasion.
MMPS AND MIGRATION ON LAMININ-5
MMPs turn laminin-5 into a motility-stimulating substrate by cleaving
its g2 subunit. We found
that MT1-MMP, a membrane-bound metalloproteinase, is the main enzyme
that cleaves laminin-5 and may regulate its turnover. In collaborations
with H. Birkedal-Hansen, National Institute of Dental and Craniofacial
Research, Bethesda, Maryland, and R. Zent, Vanderbilt University,
Nashville, Tennessee, we found that no cleavage of laminin-5 occurs
in mice that lack the gene for MT1-MMP, resulting in animals with
renal tubular dysplasia. MMP2 also cleaves laminin-5, perhaps in
an amplification loop, because MMP2 is a soluble proteinase that
is directly activated by MT1-MMP itself. These MMPs, as well as
laminin-5, are located at the leading edge of invasive tumors. In
collaboration with M. Hendrix, University of Iowa, Iowa City, we
found that MMP-induced cleavage of the g2 subunit of laminin-5 is directly responsible for the formation
of vascular-like, tumor cell-lined structures that correlate with
cancer invasiveness in vitro and in vivo.
We also investigated the value of MMPs and laminin-5 cleavage
in a normal process, trophoblast invasion, by using a custom-made
microarray system developed in-house with the help of S. Head of
the DNA Array Core Facility at TSRI. Gene profiles of invasive and
noninvasive trophoblast cells yielded interesting candidate genes
that are being evaluated for function in motility.
IDENTIFICATION OF INTEGRIN-BINDING SITES ON LAMININS
An outstanding issue in cell adhesion is the detailed structure
of integrin-binding sites on laminins. We identified a binding site
on the LG3 module of the laminin-5 a3 subunit, and we are minimizing the site to its essential
features by using a bioinformatics-guided experimental approach.
We also located a second integrin-binding site on the LG4 module.
This surprising finding may result in novel insight into how interactions
between integrins and laminins modulate cell adhesion and migration.
GINGIVAL EPITHELIAL CELL ADHESION ONTO TOOTH SURFACES
Adhesion of gingival epithelial cells onto tooth surfaces is also
mediated by laminin-5. In collaboration with S. Kinder-Haake, University
of California, Los Angeles, we found that these epithelial adhesion
mechanisms may be targeted by oral bacteria that cause periodontal
disease. We are characterizing the biochemistry of intracellular
pathways involved in disabling cell adhesion that are triggered
by these pathogens, because the pathways may yield important information
on cellular mechanisms that underlie the organization of epithelial
tissue.
PUBLICATIONS
Bilban, M., Buehler, L., Head, S., Desoye, G., Quaranta, V.
Defining signal thresholds in DNA microarrays: exemplary application
for invasive cancer. BMC Genomics 3:19, 2002.
Bilban, M., Buehler, L.K., Head, S., Desoye, G., Quaranta,
V. Normalizing DNA microarray data. Curr. Issues Mol. Biol.
4:57, 2002.
Faccio, R., Grano, M., Colucci, S., Villa, A., Giannelli, G.,
Quaranta, V., Zallone, A. Localization and possible role of
two different avb3 integrin conformations
in resting and resorbing osteoclasts. J. Cell Sci. 115:2919, 2002.
Hendrix, M.J., Seftor, E.A., Kirschmann, D.A., Quaranta, V.,
Seftor, R.E.B. Remodeling of the microenvironment by aggressive
melanoma tumor cells. Ann. N. Y. Acad. Sci., in press.
Hintermann, E., Haake, S.K., Christen, U., Sharabi, A., Quaranta,
V. Discrete proteolysis of focal contact and adherens junction
components in Porphyromonas gingivalis-infected oral keratinocytes:
a strategy for cell adhesion and migration disabling. Infect. Immun.
70:5846, 2002.
Kiosses, W.B., Hahn, K.M., Giannelli, G., Quaranta, V.
Characterization of morphological and cytoskeletal changes in MCF10A
breast epithelial cells plated on laminin-5: comparison with breast
cancer cell line MCF7. Cell Adhes. Commun. 8:29, 2001.
Quaranta, V. Motility cues in the tumor microenvironment.
Differentiation, in press.
Zent, R., Bush, K.T., Pohl, M.L., Quaranta, V., Koshikawa,
N., Wang, Z., Kreidberg, J.A., Sakurai, H., Stuart, R.O., Nigam,
S.K. Involvement of laminin binding integrins and laminin-5
in branching morphogenesis of the ureteric bud during kidney development.
Dev. Biol. 238:289, 2001.
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