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ТYИIН
АКАДЕМИК Н.И. ИЗИМБЕРГЕНОВ
КАЗ1РГ1 МЕДИЦИНАНЬЩ ЖАКА ЭТИКАЛЫК-ДЕОНТОЛОГИЯЛЫК МЭСЕЛЕЛЕР1
Марат Оспанов атында^ Батыс К,азак,стан мемлекетпк медицина университету Ак,тебе, К,азак,стан
Медициналык, этика жэне деонтология - кр«мдык, мораль, этиканын, бiр белiмi. Сондык,тан, ^ам саласында^ идеологиялык,, рухани езгерiстерге байланысты дэр^ерлт этикалык, деонтология да езгерiп турды. Сон^ы кездерi елiмiзде жана кр«м пайда болды, жана кр«мдык, сана, идеология калыптасты, адам емiрiндегi кундылык,тар езгердi. Осыfан байланысты медициналык деонтологияда жана талаптар, мэселелер пайда болды. Жумыста осы мэселелер талк,ыланfан жэне олардын шешу жолдары керсетiлген.
Нег'зг'! свздер: дэрiгердiн беделi, суркостардын дэрiгерге сенiмi, деонтологиянын жана мэселелер'1, БАЦ (СМИ) жэне медициналык, деонтология.
% SUMMARY
| ACADEMICIAN N.I. IZIMBERGENOV
NEW ETHICAL AND DEONTOLOGICAL ISSUES | OF MODERN MEDICINE
West Kazakhstan Marat Ospanov State Medical ^ University, Aktobe, Kazakhstan
Medical ethics being a branch of knowledge is a part of ^ the public morals and ethics. Therefore, changes in society, ^ ideology and social consciousness cause changes in medical ^ ethics. The paper discusses the new challenges of medical ethics ^ conditioned upon changes in modern society, social ideology,
^ depreciation of moral values in people's lives and the ways of
^ their solution are given.
^ Key words: doctor's credibility, faith in the doctor's
^ capabilities, new challenges of ethics, mass media and medical
^ deontology.
UDC: 616-006.6-07
ALLAHVERDI SHAHVERANOV
THE PROGNOSTIC AND DETECTION FEATURES OF CIRCULATING TUMOR CELLS
Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
Shahveranov Allahverdi U. - PhD student, Department of Comprehensive Oncology, email: a.shahveranov@gmail.com, tel.: +8613071240093
Abstract. The presence of circulating tumor cells (CTC) in solid tumors might be associated with stem cell-like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, to be able to disseminate and metastasize, CTC must be able to perform epithelial-mesenchymal transition. The prognostic significance of CTC counts is now well documented in multiple indications by the CellSearch assay, where CTC counts above a threshold define an unfavorable prognostic group. The ability to capture and study CTCs is an emerging field with implications for early detection, diagnosis, determining prognosis and monitoring of cancer, as well as for understanding the fundamental biology of the process of metastasis. The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of modern science. In this review an association of baseline CTC number with clinical characteristics and survival in solid tumor patients has been evaluated.
Key words: circulating tumor cells, cancer, isolation techniques.
The metastatic cancer consists ^ these cells proliferate and grow such ^ of millions or billions cells with diverse ^ as cancer stem cells which could not ^
genetic mutations driving them to grow, ^ colonize in the adherent environment divide, and invade the local tissues in ^ through tissue systems. Several cancer which they are embedded. However, ^ cells are getting shed off the edges of the
cancer tissues and are disposed of by the circulatory system or lymphatic system. In cutting-edge cancer biology terminology, these cells are called Circulating Tumor Cells (CTCs) could remain loose in circulation, cluster together as they travel, or lodge themselves in new tissues. The path and common origin of CTCs means that CTCs hold information about primary or secondary tumor, information that researchers think could be key to cancer diagnosis or treatment.
In most cases metastatic neoplastic patients possess approximately between 5 and 50 CTCs per teaspoon of blood, thus an existence of CTCs is upstaged by different blood cells. However, in the past decade emerging technologies have, for the first time, allowed the isolation of CTCs from the blood samples of patients.
Some methods, among the first established, rely on the cells' physical
properties. When a blood sample settles ^ or is spun in a centrifuge, red blood cells, ^ white blood cells, and other components ^
of blood separate into layers. Based on ^ their buoyancy, CTCs can be found in the ^
white blood cell fraction. Then, because ^ CTCs are generally larger than white ^ blood cells, a size-based filter can divide ^ the cell types (1). |
More recently, developed CTC ^ isolation techniques have depended on ^ antibodies against epithelial cell-adhesion ^ molecule (EpCAM), a protein that sticks ^ out of the outer surface of CTCs, but not ^ healthy blood cells. The Food and Drug ^ Administration approved CellSearch ^ platform, for example, consists of EpCAM ^ antibodies attached to magnetic beads (2), so the cells can be pulled out of ^ solution with a magnetic field. Among ^ other set-ups of cell-capture devices
microfluidic ^
using the antibodies, a silicon chip has been designed with tens of thousands of EpCAM antibody-coated microposts (3) for CTCs to bind to as blood ^ samples flow through the chip. Currently, ^ micrometastasis detection by molecular ^ and immunological methods, even with tumor-specific mRNA or antigen, ^
does not provide information regarding ^ the number of cells, cell viability, the ^ ability of the cells to adhere and produce metastatic deposits, and the resulting immune response to the cells. Many ^ factors are being discovered as important
a Positive selection
Anti-E marker antibody (e.g. EPCAM)
Anti-E and anri-M marker antibody (e.g. plait in 3)
c Filtration
Anti-M marker antibody ,<), N-cadherifi)
in metas-tasis formation. In prostate cancer, for example, numerous molecular and cellular abnormalities are associated with tumor progression, including various chromosomal defects (8p-, lOp-, lOq-, lOq-, and l8q), p53 mutation, decreased expression of the KAII suppressor gene, BCL-2 expression, Lewis Y antigen expression, decreased expression of MHC I and II determinants, CD44 expres-sion, increased expression of proliferation markers.
As these methods for isolating CTCs mature, correlations between the cells and a patient's disease have emerged. In 2004, researchers discovered that breast cancer patients with fewer CTCs in their blood lived longer than those with more CTCs (4). Similar results have been seen in other cancer types, including prostate and colorectal cancers (5). Further investigations have been sorted out the genetic mutations that the cells carry, comparing the mutations to those in a primary cancer tissue or correlating the findings to a patient's disease severity or spread. In one study, lung cancer patients whose CTCs carried a mutation known to cause drug resistance had faster disease progression than those whose CTCs lacked the mutation(6) which is described in conceptual view (Figure1). Relevant studies describe the important association between high serum CTC levels and quite shorter overall survival b Negative selection
Ex vivo
• CellSearch® system
• MagSweeper'"
• EPHESIA CTC-chip
• CTC-chip
• Velcro-Üke device
)rt vivo
- CellCollector® • Photoacoustic nanodetector
rates in advanced cancer patients with metastatic breast, lung, and prostate carcinomas. In another study, changes to certain signaling pathways within CTCs during treatment could predict how well prostate cancer patients responded to a drug (7).
Taken together, the results suggest that CTC blood tests could be use to track the severity of a cancer or efficacy of a treatment. The other investigations based on isolated CTCs both forward genomical and physical features have been underpinned novel drug targets.
In the advanced stages of metastatic cancer in the patients it is significant to develop the treatment types that could modulate not solely proliferation but also invasion and migration which is very substantial characteristics of the metastatic process.(8) The conventional factors recently utilized for prognostic evaluation and management strategies in the advanced stages of prostate, colon, and breast cancer, which consisting of hormone receptor and HER2 status, location and extent of metastatic process burden, and duration of disease-free interval which usually do not efficiently anticipate treatment response and disease evolution.(9) The association between CTCs and metastatic disease such as their property to anticipate overt metastatic dissemination, may have important affects in the clinical
Physical and biological properties
Antibody
against
CD45
d Chip
e Ficoll gradient
f Electric field
White л Magnetic blood cell " bead
Figure 1: The conceptual framework of CTC assays and point out current challenges of CTC research, which might structure this dynamic field of translational cancer research.
Credit: Nature Reviews Cancer 14,623-631 (2014)
therapeutic features in patients with ^ CK/CD133 positivity as compared with ^ breast cancer, and most CTCs have stem
advanced metastatic disease.(10,11) those with negativity. In all patients with cell phenotypes that are nonproliferating
Furthermore, the patients with ^ Dukes' stage B cancer, the OS and DFS of ^ and resistant to chemotherapy. (15) The
specific condition, pre- and post- ^ those with CEA/CK/CD133 positivity were ^ surface markers of colon cancer stem
treatment CTC counts have been significantly worse than those of patients cells, CD133, CD44, CD166, Musashi-1,
associated with higher risk of improving ^ who were negative for these markers. ^ CD29, CD24, leucine-rich repeat-
recent metastatic locations and injuries ^ TAMs are recruited by various cytokines ^ containing G-protein-coupled receptor 5,
during the management insufficiency. ^ and chemokines, suppress the activity of ^ and aldehyde dehydrogenase 1 molecules
This could intend limited evaluation cytotoxic T-lymphocytes via programmed have been reported,29-32 and the CD133
of complex management modalities ^ cell death 1 ligand 1 (PD-L1) or B7-H4 ^ molecule has emerged as the key marker
that consists local therapy features in and other receptors/mediators. (13) for enriching cancer stem cells in many
patients with high CTC counts. CTCs The mechanisms by which macrophages types of cancer.(16,17,18) In contrast,
recruit immunosuppressive cells, ^ acquire prometastatic abilities have not ^ other publications have suggested that
particularly belonging to the myeloid- ^ been fully characterized. If measurable ^ CD44 may be a more specific marker for
macrophage lineage, which undergo ^ changes in some CTCs make them more ^ colon cancer stem cells.(19) It is known
functional polarization in dependence likely to lodge in a new tissue, spreading that CD44 is expressed not only in cancer
of tumor-derived factors. These tumor- ^ a cancer, then blocking such changes, or ^ stem cells but also in a variety of other
educated macrophages promote killing circulating cells that show these cells including blood cells.(20) Because
invasion, intravasation as well as survival signs, could stop cancer metastasis. our study did not separate the cancer
in the circulation and durable growth Whether CTCs have stem cell features is cells from blood cells, it was difficult to
at secondary lesions.(12) To clarify the of interest. The cancer stem cell concept measure the CD44 that originated in
clinical significance of CD133 addition hypothesizes that tumors arise from a the cancer cells. Therefore, we selected
in patients with Dukes' stage B and C small population of stem cells, and it CD133 for the genetic marker of cancer
cancer, the analyze of the OS and DFS ^ has been assumed that the founder cells ^ stem cells. CD133 belongs to the prominin
in the general CTC markers (CEA, CK19, of metastases may also be stem cells family of proteins, the function of which
and/or CK20: CEA/CK), and in the CD133 ^ disseminated from the primary tumor to ^ remains unknown. It has a novel isoform
single marker. In patients with Dukes' ^ a distant metastatic site. This hypothesis ^ that follows the detection of a small exon
is supported by the similarities between
in OS and DFS were found between those the properties of CTCs and cancer stem ^ splicing. Conversely, CD133 is known
stage B cancer, no significant differences is supported by the similarities between of 27 nucleotides by alternative mRNA
^ 4-U« «f rTTr' ^
who were positive for CEA/CK and those ^ cells, which suggests that the founder | as a marker of endothelial progenitor
who were negative for CEA/CK, nor were ^ cells of metastases arise from the CTC ^ cells, which are capable of expanding
significant differences seen between ^ population. It has been reported that stem ^ more than 1,000-fold and initiating
patients who were positive for CD133 as ^ cell markers are frequently overexpressed ^ the premetastatic niche.(21) Although
compared with those who were negative in the CTCs of patients with metastatic the present assays are not designed to
for CD133. Furthermore, when patients ^ breast cancer, and most CTCs have stem ^ differentiate CD133-positive cancer stem
with Dukes' stage B and CEA/CK/CD133 ^ cell phenotypes that are nonproliferating ^ cells from endothelial progenitor cells,
positivity who were considered to be and resistant to chemotherapy. (14) ^ we assume that cytokeratin-negative
at high risk were separated out on the ^ Whether CTCs have stem cell features is ^ aggressive CTCs may be included in the
basis of factors such as perforation or of interest. The cancer stem cell concept CD133-expressing cells. (22) obstruction and/or lymphatic invasion, ^ hypothesizes that tumors arise from a ^ Different methods to detect CTCs
they demonstrated significantly worse OS ^ small population of stem cells, and it ^ in patients with carcinoma have been
and DFS than patients who were negative ^ has been assumed that the founder cells ^ developed.(23,24) Previous studies have
for these markers. In patients with Dukes' ^ of metastases may also be stem cells ^ used indirect molecular methods such
stage C cancer, the OS and DFS of the ^ disseminated from the primary tumor to ^ as reverse transcription-polymerase
group with CEA/CK/CD133 positivity were ^ a distant metastatic site. This hypothesis ^ chain reaction (RT-PCR), quantitative
significantly worse than those of patients is supported by the similarities between RT-PCR (qRT-PCR) and nested RT-PCR or
who were negative for these markers. OS the properties of CTCs and cancer stem have used indirect immunomediated
and DFS at each tumor stage according ^ cells, which suggests that the founder ^ methods using immunolabeling of
to the PCR status in the training set. cells of metastases arise from the CTC cells enriched by different approaches
In patients with Dukes' stage A cancer, ^ population. It has been reported that stem ^ including immunomagnetic separation
there were no significant differences ^ cell markers are frequently overexpressed ^ with magnetic beads coated with
in OS and DFS in the patients with CEA/ ^ in the CTCs of patients with metastatic ^ epithelial-specific antibodies (BerEP4,
EpCAM), laser scanning cytometry and, of the cell.11 Currently, direct methods the CellSearch system in patients with more recently, a microfluidic device (the are more rarely used for CTC detection. metastatic breast colorectal and prostate CTC chip). qRT-PCR- and nested RT-PCR- | (26,27) | cancer. J Oncol 2010:617421.
based methods analyze the expression of ^ Conclusion: ^ 6. Maheswaran S, et al. (2008)
a given transcript marker, compared to a ^ CTC markers that could signal ^ Detection of mutations in EGFR in reference marker expressed in any cell, ^ metastasis and could provide novel drug ^ circulating lung-cancer cells. N Engl J Med which would be indicative of the presence |s targets have been found in mouse models |s 359(4):366-377.
targets have been found in mouse models
of tumor cells. CTCs can be detected by ^ of pancreatic cancer and blood samples ^ 7. Miyamoto DT, et al. (2012)
CS and ISET in NSCLC patients undergoing ^ from breast cancer patients. Summary of ^ Androgen receptor signaling in circulating
radical surgery. Only a fraction of this ^ expected clinical usability of CTC analysis ^ tumor cells as a marker of hormonally population had simultaneous detection of ^ is based on determination of the need ^ responsive prostate cancer. Cancer Discov
CTCs by ISET and CS, but the percentage for aggressive treatment by the number 2(11):995-1003.
of patients with detected CTCs is higher of CTCs in blood before treatment. The 8. Yu M, et al. (2012) RNA
when combining the two methods. This epithelial-to-mesenchymal transition sequencing of pancreatic circulating
result underlies the complementarity ^ (EMT) can cause alteration of cellular ^ tumour cells implicates WNT signalling in
of the two methods for detecting CTCs features and loss of epithelial properties metastasis. Nature 487(7408):510-513.
preoperatively. CS failed to detect CTCs leading to a partial or complete 9. Yu M, et al. (2013) Circulating
expressing only vimentin, which can be switch to a mesenchymal phenotype. breast tumor cells exhibit dynamic
observed when using ISET. Moreover, the Particularly stem cells have the ability changes in epithelial and mesenchymal
main advantage of these methods is the to take on characteristics of other cell composition. Science 339(6119):580-
higher sensitivity in comparison with the types. So far, CTC detection methods 584.
reported sensitivity of immune-mediated ^ consist of enrichment and subsequent ^ 10. Parkinson DR, Dracopoli N,
detection.(25) Conversely, direct methods ^ identification mostly with anti-cytokeratin ^ Petty BG, Compton C, Cristofanilli M, contribute to diagnostic identification of ^ (CK) or epithelial cell adhesion molecule ^ Deisseroth A, Hayes DF, Kapke G, Kumar
CTCs. ISET technology is a direct method (EpCAM) antibodies. An assessment of P, Lee J, Liu MC, McCormack R, Mikulski
that allows cytomorphological analysis ^ expected treatment effect by the number ^ S, Nagahara L, Pantel K, Pearson-White
of CTCs.11 For this reason, it offers a ^ of CTCs in blood after the first treatment. ^ S, Punnoose EA, Roadcap LT, Schade
number of advantages, particularly for ^ References: ^ AE, Scher HI, Sigman CC, Kelloff GJ:
immunocytochemical examination using ^ 1. Vona G, et al. (2000) Isolation ^ Considerations in the development of
different antibodies to better characterize ^ by size of epithelial tumor cells: A new ^ circulating tumor cell technology for
the CTCs. However, some CTCs may loss ^ method for the immunomorphological ^ clinical use. J Transl Med. 2012, 10: 138-
a certain number of antigens normally ^ and molecular characterization of ^ 10.1186/1479-5876-10-138.
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ТYИIН | РЕЗЮМЕ
АЛЛАХВЕРД1 ШАХВЕРАНОВ I АЛЛАХВЕРДИ ШАХВЕРАНОВ
аИналымдагы обыр жасушаларын болжау жэне | особенности прогнозирования и определения
аньщтау ерекшел1ктер1 | циркулирующих раковых клеток
Тонжи ауруханасы, Тонжи медициналык колледжi, Хуажон ^ Больница Тонгжи, Медицинский колледж Тонгжи, Хуажонг
^лым жэне технология университетi, Ухан, Кытай ^ Университет Науки и Технологии, Ухань, Китай
Солидт iсiктерде айналымда жYретiн iсiк клеткасынын ^ Наличие циркулирующих опухолевых клеток (ЦОК)
(А1К) болуы - бiрiншiлiк iсiктiн метастаз берушщ белсендi ^ в солидных опухолях может быть связано с опухолевыми
кeзi ретЫде vсынылfан баfаналы клеткаларfа уксас ^ клетками, подобными стволовым клеткам, которых
iсiк клеткаларына байланысты болуы мYмкiн. Сонымен ^ предлагают рассмотреть как активный источник
катар, А1К-да таралу жэне метастаздану жаедайы болуы ^ метастазирования в первичных опухолях. Кроме того, чтобы
Yшiн, бул клеткалар эпителиалды-мезенхималды кешу ^ иметь возможность распространяться и метастазироваться,
к,ызметш аткаруы тиiс. А1К санау эдiсiнiн болжам жасаудаfы ^ ЦОК должен быть в состоянии выполнять функцию
маныздыль^ы казiргi танда fылыми эдебиеттерде жаксы ^ эпителиально-мезенхимального перехода. Прогностическое
кершк тауып, Се1^еагсЬ| анализi аркылы есептеледi. Егер ^ значение подсчета ЦОК теперь хорошо документированы
де А1К кeрсеткiшi шект денгейден жоfары болса, колайсыз ^ в многочисленных исследованиях с использованием
болжамды iсiк тобы болып есептеледГ А1К-ы аныктау жэне ^ Се1^еагсЬ| анализа. Если показатель ЦОК выше порогового
зерттеу - iсiктi алfашкы сатысында табу, диагностикалау, ^ значения, то он относится к группе с неблагоприятным
болжамын бту жэне бакылау Yшiн, сонымен катар, ^ прогнозом. Возможность описания и изучения ЦОК
метастаздану процеанщ негiзгi жэне биологиялык ^ является новой областью науки, имеющей преимущество в
механизм^ тYсiнуде артыкшылыктары бар fылымнын ^ раннем выявлении, диагностике, определении прогноза и
саласы болып табылады. Нысаналы ем эдiсiн тандау жэне ^ мониторинге рака, а также, для понимания фундаментальных
клиникалык акырын баfалау Yшiн арнайы iсiк маркерлерiн ^ и биологических механизмов в процессе метастазирования.
жасау - заманауи ^лымнын манызды саласы болып отыр. ^ Разработка специфических опухолевых маркеров для
Осы эдеби шолу макаласында солидт iсiгi бар пациенттердегi ^ выбора целевой терапии и для оценки клинического
А1К непзп кeрсеткiшiнiн клиникалык сипаттамасы жэне ^ исхода остается важной областью современной науки. В
eмiршендiк денгейше байланысы баfаланады. ^ этой обзорной статье оценена взаимосвязь базового числа
Нег'зг'! свздер: айналымдагы обыр жасушалары, | ЦОК с клиническими характеристиками и показателем
0быр, 0к,шаулау эдiстерi. ^ выживаемости у пациентов с солидными опухолями.
^ Ключевые слова: циркулирующие раковые клетки,
^ рак, методы изоляции.
