There are a series of steps that a tumor cell must go through before
metastasis can occur. After cells grow into a benign tumor in the epithelium,
genetic alterations allow them to break out through the basement membrane,
traverse through the extra cellular matrix and invade the capillary. Once tumor
cells enter the circulation they can travel through the bloodstream to a distant
site. CTCs must adhere the vessel wall, made up of endothelial cells, before
they can extravasate. if the microenvironment is established, the tumor cell(s)
may proliferate at this distant site and eventually form lethal metastases.
Previous Studies on Circulating Tumor Cells (CTCs):
Numerous studies have concluded that the presence of CTCs in the bone marrow
(BM) is of prognostic significance in different types of solid tumors. The most
extensive database on BM micrometastasis and prognosis exists for breast cancer,
involving over 4000 patients. However, the use of BM examination for CTC
detection is not yet part of routine clinical staging. This is predominantly
because several other studies found no statistically significant relationship
between CTC detection and prognosis. The most likely explanation of the
discrepancy between these studies is the technical and methodological
differences applied for CTC detection.
Since the frequency of CTCs in BM of cancer
patients can be as low as one tumor cell in a background of one million normal
hematopoietic cells, the reliable detection and quantification of such rarely
occurring cells challenges available analytical methods.
Another approach that we use for the detection of occult micrometastases is
measuring CTCs in peripheral blood (PB).
The reliable measurement of CTCs depends on both sample preparation protocol and
detection technique, and hence research in this area must take both into account
simultaneously in order to develop a reliable and clinically useful approach.
There is good reason to be optimistic about the value of CTC detection. A recent
clinical trial involving 177 metastatic breast cancer patients showed the number
of CTCs in PB after immunomagnetic enrichment provided prognostically useful
information regarding progression-free and overall survival in a subset of
patients.
Health Relevance:
Breast cancer is the most common
visceral malignancy affecting women, with 212,118 new cases estimated for 2005
in the United States. Breast cancer survival is determined primarily by stage of
disease at diagnosis, with 92%, 73% and 13% overall survival at 5 years for
localized, node positive and metastatic disease, respectively.
Current tumor staging parameters are only able to statistically predict the
risk of recurrence for populations of patients without giving indications about
the possible outcome for any one individual, which, after complete surgical
excision of localized disease, is primarily influenced by the presence of
unidentified disseminated circulating tumor cells. It has been estimated that
most breast cancer metastases are initiated early, when the primary tumor is
less than 0.2 cm3 in volume and clinically classified as local disease. In fact,
breast cancer cells are detected in the bone marrow of 33% of breast cancer
patients with node negative disease. Identification of patients at higher risk
for relapse is essential so that more aggressive therapy tailored according to
the patient’s needs can be initiated.
Another potential application of CTC detection
from PB is the early diagnosis of cancer.
At some ill-understood point during primary tumor growth, invasive
sub-populations of the primary tumor cells gain access to the circulation. While
the literature supports the concept that many tumor cells shed from a primary
tumor are immediately destroyed in the circulation and most shed cells do not in
fact result in metastasis, detection of such shedding may provide an early clue
as to the presence of malignancy . With ancillary use of appropriate tissue
and/or organ specific markers, CTC screening could be an early indicator of
metastasis-capable malignancy.
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