Research Report 2000 - MDC

Surgical Oncology
Peter M. Schlag
Tumor progression, invasion
and metastasis
W. Kemmner, U. Stein, W. Walther,
W. Haensch, H. Schwabe
in cooperation with U. Karsten,
J. Behrens, W. Birchmeier
Tumor-associated alterations of cell
surface glycosylation play an
important role in invasion and
metastasis of carcinoma cells.
Accordingly, expression of the
glycosyltransferases responsible for
glycosylation is altered in tumor cells
and this influences their cell adhesion
properties. Therefore, sense- and
antisense- transfectants of such
glycosyltransferases have been
established. Specific antisense
oligodeoxynucleotides, which inhibit
enzyme activity have been studied in
connection with a possible clinical
treatment of metastasis. Another of
our interests are Thomsen-
Friedenreich (TF) related tumorassociated
carbohydrates. We have
found that the balance between Oglycan
chain termination through
sialylation and chain extension
through N-acetylglucosaminylation is
disturbed in colorectal carcinomas.
Patients with high expression of
sialyltransferase ST6GalNAc-II are at
a significantly higher risk of death and
have a shorter overall survival.
We have identified new genes
involved in the organ-specific
metastases of colon carcinoma by
differential display using surgical
specimens. Three ESTs have been
identified that are differentially
expressed in metastasizing versus
non-metastasizing primary tumors,
distinct metastases (preferentially liver
and lung) or normal epithelium.
Expression of candidate genes was
confirmed by quantitative real time
RT-PCR.
Expression of the transcription factor
GLI has been analyzed in sarcomas
and during metastasis and we found
significantly enhanced GLI expression
in tumors compared with normal
tissues. Moreover, GLI expression
correlated with the grading of the
sarcomas. Thus, enhanced GLI
expression might be indicative of
aggressiveness and dedifferentiation
of mesenchymal tumors.
Multidrug resistance and
hyperthermia
U. Stein, W. Walther, K. Jürchott
in cooperation with B. Rau,
P. Hohenberger, P.-U. Tunn
Multidrug resistance (MDR) still
limits the successful chemotherapy of
cancer. The expression of MDRassociated
genes is inducible by
external stress factors such as heat
shock. This is controlled by stress
responsive elements within the gene
promoters and might be a molecular
mechanism that hinders
chemotherapy. Thus, the impact of
hyperthermia on the induction of
MDR-associated genes has been
investigated in colorectal carcinomas,
before and after radiochemotherapy or
radiochemothermotherapy,
respectively. In the majority of the
cases analyzed, the risk of inducing
MDR gene expression by
hyperthermia has been found to be
minimal in a clinical setting.
Investigations analyzing the influence
of hyperthermia on the expression of
the MDR genes, 2 – 48h following
heat treatment, are currently
underway. The impact of isolated
hyperthermic limb perfusion on the
expression/induction of MDRassociated
genes had been examined
in soft tissue sarcomas and
melanomas at several time points
prior to, during and post treatment. So
far, induction of certain MDRassociated
genes, such as MDR1,
MRP1, and LRP, has been observed
within hours of hyperthermic
treatment. Heat shock-induced
expression of MDR genes should be
taken into account when combining
hyperthermia with MDR-associated
cytostatic drugs.
Detection and pathobiology of
solid tumors with microsatellite
instability
K. Kölble, B. Barthel, L. Estevéz-
Schwarz, K. Krause, H. Pidde,
O. M. Ullrich in cooperation with
M. Dietel and S. Scherneck
Somatic alterations in simple
repetitive sequences that are present
as microsatellites throughout the
human genome are characteristic of a
subset of human tumors with defects
in DNA mismatch repair. Germline
mutations in various DNA mismatch
repair genes dramatically increase an
individual’s susceptibility to various
neoplasms and are the molecular basis
for the syndrome of hereditary nonpolyposis
colorectal carcinoma
(HNPCC). HNPCC is characterized
by the early and familial occurrence
of intestinal and extraintestinal
cancers. Collaborative efforts to better
define the epidemiological, clinical
and pathomorphologic features of this
cancer susceptibility syndrome are
critical for elucidating its pathogenetic
pathways and improving the clinical
management of patients and gene
carriers. Potential cases of HNPCC,
reported locally as well as regionally,
have been registered and investigated
by a combination of detailed clinical
and pedigree studies, histopathology,
immunohistology, microsatellite
instability (MSI) analysis and
germline sequencing. However,
identification of HNPCC carriers by
biochemical screening prior to
complete genomic sequencing could
significantly improve these existing
cancer preventive strategies. Cell-free
DNA in the blood of cancer patients
has been shown to harbor
microsatellite alterations frequently
matching those of the primary tumors.
We have investigated the patterns of
such microsatellite alterations in sera
and microdissected tumors of
colorectal cancer patients. Using an
integrative morphological,
immunohistological and genetic
approach, high-grade serum MSI was
preferentially found in individuals
with mismatch repair-defective
tumors. Although the molecular
mechanisms of tumoral DNAshedding
remain to be elucidated, its
detection by serum DNA
microsatellite analysis appears to be
useful for the diagnosis and
monitoring of neoplasms caused by
defective DNA mismatch repair.
The subsequent development of a
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