الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Breast tumors are well known to be composed of phenotypically diverse groups of
cells; however, it is unclear which of these cell types contribute to tumor development. In
contrast to the hypothesis that all cell populations have the capacity to become tumorigenic
through accumulation of mutations, another hypothesis limits this ability to an elite group
of cells that share classic features of stem cells. There is increasing evidence suggests that
the existence of a small population of specialized cancer cells that display stem-cell
properties, commonly referred to as cancer stem cells (CSCs) or cancer initiating cells.
CSCs are characterized by their ability to self-renew, differentiate into various lineages,
and reconstitute the cellular hierarchy of the tumor from which they are derived in serial
xenotransplant assays. These cells are highly resistant to chemo- and radiotherapy and are
believed to be responsible for tumor recurrence following therapeutic intervention.
Aim of the work:
In the present study, we attempted to investigate the role of cancer stem cell marker
CD44 and its ligand HA in breast cancer patients and their impact on apoptosis stimulating
protein P53 and VEGF.
Subjects and methods:
Fourty female patients who were newly diagnosed with BC were enrolled into the
study as patient groups. Fourty women with normal mammography findings and no
previous history of any kind of cancer with matched age and menopausal status served as
control group.
Venous blood sample was collected concurrently from each breast cancer patient
(Before surgery) and from the control group. All blood samples we obtained at fasting
early in the morning and the serum was immediately separated by centrifugation and stored
at -70° until use. Serum hyaluronan, p53 and VEGF levels were measured by enzyme
linked Immunosorbent assay. Tumor tissue was collected from each patient with breast
cancer and tissue expression of CD44 was evaluated by immunohistochemical staining for
malignant group. Patients were followed up clinically, radiologically and by laboratory
testing for 24 months to assess the prognostic value of the markers.
Results and Discussion:
According to the results of the present study, the expression of CD44 protein was
examined in BC tissues of 40 BC patients and 40 adjacent normal control tissues. The
result offered evidence that CD44 protein was remarkably expressed in 70% of breast tumor
tissues in comparison with normal counterparts at protein level indicating that CD44 might
participate in the tumorigenesis of breast cancer.
Additionally, our results suggest a positive significant correlation between
histological grade and the CD44 protein expression levels. This would indicate these
patients with high CD+
44 protein abundance might have poor prognosis, because high grade
Summary and Conclusions
82
tumor tends to be more aggressive and tends toward early recurrence. Moreover, CD44
protein abundance tended to be positively significantly correlated with clinical stage
indicating that this molecule may be considered as a biological tumor marker for
estimating the occurrence and progression of BC regardless of treatment. It was
demonstrated that CD44 tended to be negatively correlated with ER, PR and truly
associated with HER2 which are already tested as poor prognostic markers. Therefore CD44
might play an important role in breast tumor genesis and malignant transformation.
According to a survival analysis the results showed that patient whose tumors coexpressed
CD+
44 were prone to have shorter disease-free survival time than CD-
44 tumors.
The log rank value was (4.841). Our data indicated that CD+
44 might be used as a
biomarker to predict patient who are at increased risk for progression of cancer metastasis
or relapse.
The present study revealed that serum HA levels are highly elevated in breast cancer
patients in comparison to control group with significant elevation in patients with positive
CD44 protein expression than CD44 negative patients. This result is expected since HA is
synthesized from carcinoma cells and stromal cells which are also a rich source of this
biopolymer and may point to the role of CD44 in up-regulating HA. Furthermore, it was
noticed that serum HA was positively correlated with histological grade and vascular
invasion and negatively correlated with ER and PR expression. These results clearly
showed the role of HA in carcinogenesis and progression of breast cancer.
In this study the relationship between serum HA and prognosis was analyzed by
evaluating DFS in total 40 female patients. The analyses of DFS showed that higher level
of this parameter is significantly associated with poor prognosis in patients with breast
cancer.
In the current study, we found a close relationship between VEGF and CD44. Patients
with positive CD44 protein expression had a mean serum VEGF that was significantly
higher than either breast cancer patients with negative CD44 expression or healthy controls.
Thus, we draw a conclusion that CD+
44 served as an up-regulator of VEGF to function in
the progression of BC. Therefore the results suggest that CD+
44 protein abundance may be
critical for driving angiogenesis by secreting VEGF.
Our study revealed that in all breast cancer patients p53 levels were significantly
lower than in control group. Moreover, decreased p53 serum levels are associated with
elevated CD44 protein expression in breast cancer patients. These findings lead us to
suggest that aberrant CD44 protein expression is advantageous for the growth, survival and
dissemination of tumor cells.