Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2023 | Month : January | Volume : 17 | Issue : 1 | Page : XE01 - XE06 Full Version

Activated Leucocyte Cell Adhesion Molecule (CD166): A Biomarker in Diagnosis and Prognosis of Breast Cancer


Published: January 1, 2023 | DOI: https://doi.org/10.7860/JCDR/2023/59550.17359
Vemareddy Hemalatha, Bhawna Dev, N Vanitha Rani, MG Rajanandh

1. Research Scholar, Department of Pharmacy Practice, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India. 2. Professor, Department of Radiology and Imaging Sciences, Sri Ramachadra Medical Centre, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India. 3. Former Assistant Professor, Department of Pharmacy Practice, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India. 4. Associate Professor (Research), Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Thandalam, Chennai, Tamil Nadu, India.

Correspondence Address :
Dr. MG Rajanandh,
Associate Professor (Research), Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Thandalam, Chennai, Tamil Nadu, India.
E-mail: rajanandh.mg@sriramachandra.edu.in

Abstract

The global incidence of breast cancer and associated mortality is rising annually despite advanced diagnostic aids and treatment methods. This is due to the failure and difficulty in detecting the disease at an early stage. Due to an increase in the breast cancer mortality rate, biomarkers associated with early and prompt detection are being extensively studied, owing to their sensitivity, specificity, cost-effectiveness, and minimally invasive or non invasive analysis. Among those carbohydrate antigens, carcinoembryonic antigens, and circulating tumour cells are the most commonly observed serum biomarkers in the detection of cancer. In recent years, extensive research is carried out on cell adhesion molecules and their role in the process of cell adhesion which is essential for the development and homeostasis in multicellular organisms. These cell adhesion molecules accelerate appropriate cell response and intercellular communication. Activated Leucocyte Cell Adhesion Molecule (ALCAM) or Cluster of Differentiation 166 (CD166) is a transmembrane glycoprotein and emerging as a promising biomarker for primary detection of tumour cells with metastatic potential and is also upregulated in breast tumours. This review ascertains the usefulness of the ALCAM as a potential diagnostic and prognostic marker for early detection, classification, and prognosis of breast cancer and also elucidates the role of the various other biomarkers.

Keywords

Cluster differentiation 166, Early detection, Transmembrane glycoprotein

Breast cancer accounts for nearly 25% of female malignancies and their prevalence is higher in developed countries in recent years (1). According to the World Health Organization (WHO), 2.3 million women were diagnosed with breast cancer in 2020, with 685000 deaths worldwide; by the end of 2020, there were 7.8 million women alive who had been diagnosed with breast cancer in the previous five years, making breast cancer the world’s most prevalent cancer (2). In India, an estimated 1,62,468 women were newly diagnosed with breast cancer in 2018. In India, 87,090 women died of breast cancer in 2018, the second-highest number in the world for that year (3). Breast cancer in young women is associated with relatively aggressive pathophysiology and also has a poor prognosis when compared to that of older women. A mammogram is a vital tool for breast cancer screening, but it has concerns about radiation exposure and high false positive and false negative results (4). In addition, mammograms cannot detect small tumours and give inaccurate results in women with dense breasts (5).

Biopsy, either as a needle or surgical invasive procedure is done for confirmation of breast cancer, which is not required in benign tumours (6). The current trend of usage of biomarkers for breast cancer detection has brought a safe solution to this problem (7). Much research is being conducted for the development of non invasive biomarkers to aid in early breast cancer detection. Circulating biomarkers like Carcinoma Antigens (CA), Circulating Tumour Cells (CTC), micro-Ribonucleic Acid (miRNA), cell-free tumour nucleic acids {Deoxyribonucleic Acid (DNA)/ Ribonucleic Acid (RNA)}, in the peripheral blood, sweat, urine, tears, saliva, nipple aspirate fluid, as well as Volatile Organic Compounds (VOC) in breath, are all potential candidates of non invasive early breast cancer detection methods (8). Carbohydrate Antigen (CA15-3) and Carcinoembryonic Antigen (CEA) are the commonly used serum biomarkers in breast cancer detection and prognosis assessment (9). Extensive research is being carried out in this area and significant progress has been made.

Many studies report that these biomarkers lack sensitivity and specificity in detecting the early stages of carcinoma (8). Activated Leucocyte Cell Adhesion Molecules (ALCAM) or Cluster of Differentiation (CD166), a member of the immunoglobulin superfamily, mediates cell to cell clustering and also influences cellular growth, cell differentiation, junction formation, and polarity. This has different names depending on the species and laboratory that described it: chicken neural adhesion molecule BEN/SC-1/DM-GRASP, rat KG-CAM, fish neurolin, human melanoma metastasis cloned, Mouse/Human CD166 and rat HB2 (10). This is found to be expressed in many types of cancer and is proved to possess high specificity in breast cancer (10),(11). Studies show a positive correlation between high levels of ALCAM and an early prognosis in breast cancer patients (12). Early detection and prognosis assessment play a pivotal role in reducing mortality associated with breast cancer. The development of a simple and convenient non invasive test is the need of the hour to overcome the shortcomings of the existing invasive and painful breast cancer detection methods.

The present review summarises the various non invasive biomarkers in breast cancer detection and also ascertains the usefulness of ALCAM as a diagnostic and prognostic biomarker by comparing multiple authenticated published articles which might aid in the development of a promising biomarker in the near future. The current progress of research in this area has also been discussed.

BREAST CANCER

Epidemiology and Global Burden

Breast cancer ranks first among Indian females when compared with other types of cancer and has an incidence of 41 per one lakh women in Delhi. The other Indian cities with a high incidence of breast cancer are Chennai (37.9), Bengaluru (34.4), and Thiruvananthapuram (33.7) (12). A 2020 projection of breast cancer in India says that the numbers are as high as 1797900 (13). The 2022 report of the National Breast cancer Foundation, United States says that one in eight women may develop breast cancer in their lifetime. If diagnosed and treated early, breast cancer is a potentially curable disease (14).

Surveillance, Epidemiology, End Results programme (SEER programme) has reported that if breast cancer is diagnosed at stage I/II, the five year survival rate will increase by 85% to 98%. The worldwide economic impact of premature death and disability from breast cancer was $447 billion in 2008. This figure represents 0.75% of the world’s Gross Domestic Product (GDP) (15). Therefore, if early intervention and treatment are both efficient and cost-effective, the economic burden, as well as mortality rates, can be offset.

Classification of Breast Cancer and Biological Characteristics

Breast cancer has diverse etiological and pathological features; it can show slow growth but excellent prognosis in some cases, and a highly aggressive nature in other cases; based on this difference breast cancer can be classified based on tumour grade, morphology, and molecular classification (16). According to the tumour grade, breast cancer can be grade 1 or well-differentiated (slow-growing cells, looks more like normal breast tissue), grade 2 or moderately differentiated (cells grow at a speed and look like cells somewhere between grades 1 and 3), and grade 3 or poorly differentiated (cancer cells look very different from normal cells, proliferate and spread faster) (17). The two main morphologic umbrellas are based on the invasiveness and place of origin of breast cancer and are classified as invasive or in situ carcinoma; ductal and lobular carcinoma. The schematic classification based on morphology can be found in (Table/Fig 1). This grading index is called Nottingham Prognostic Index (NPI) and is a vital tool in assessing the prognosis (18). Based on its molecular genetics, breast cancer can be classified as Estrogen Receptor positive (ER+) and Estrogen Receptor negative (ER-). These are the two major molecular subtypes and many other subtypes do exist, discussing which will be out of the scope of this review. The other oncogenes associated with breast cancer are Human Epithelial Receptor-2 (HER2), c-MYC, Retrovirus Associated DNA Sequence (RAS) genes, cyclins D1 and E, and tumour suppressor genes like Retinoblastoma (RB), TP53, PTEN, Breast Cancer gene 1 (BRCA1) and Breast Cancer gene 2 (BRCA2) (19).

Risk Category and Risk Factors of Breast Cancer

There are two categories of breast cancer risk factors: major risk factors and minor risk factors. Major risk factors for breast cancer include being a woman, getting older, having a family history of the disease, and having the BRCA1 or BRCA2 gene mutation; minor risk factors include early menarche (before age 12), late menopause (after age 55), nulliparity, having a first child after 30, taking hormone replacement therapy, and eating a high-fat diet (19).

Early Detection and Screening

Mammography is the quintessential imaging technique of the present day for breast cancer evaluation that use X-ray say to produce images.

However, owing to the high false-positive results, overdiagnosis and radiation exposure mammography may not be the gold standard (20). Clinical breast examination and self-breast examination have shown some benefits in early breast cancer screening (4). Ultrasound, Magnetic Resonance Imaging (MRI), biopsy, and additional lab tests may be required for further analysis as described in (Table/Fig 2) (20),(21),(22). In addition, biomarkers supplement clinical diagnosis in the past few decades. A study by Kazarian A et al., and his team members on blood biomarkers for early detection and screening of breast cancer found that the biomarkers lacked sensitivity in predicting the disease and even the combined candidates showed consistent changes in levels (23). This is in agreement with the previous cohort studies, where a combination of up to 10 biomarkers {including Cancer Antigen 15-3 (CA15-3) and Osteopontin (OPN)} could not discriminate the breast cancer cases from control (10). Therefore, a novel biomarker that can effectively identify early-stage breast cancer still needs to be found.

BIOMARKERS OF BREAST CANCER

Despite the high incidence rate of breast cancer, the mortality rates have steadily decreased due to the better treatment options and timely early diagnosis as a result of the development of non invasive diagnostic methods that tested the body fluids for biomarkers (24). The detection of breast cancer through biomarkers is simple, economic, more feasible when compared with other detection methods. Blood, tears, sweat, Nipple Aspirate Fluid (NAF) and Volatile Organic Compounds (VOC) in the exhaled breath, saliva, and urine are potential body fluids that can supplement early breast cancer detection (25). A detailed tabulation of the non invasive biomarkers, and blood-based biomarkers and how they are sampled is shown in (Table/Fig 3) and (Table/Fig 4) respectively.

Circulating serum carcinoma proteins like CA15-3, CA-125, CEA and HER2 are associated with the proliferation, invasiveness, and oncogenic signalling of tumour cells and are effective markers of advanced cancer detection (26). They have low diagnostic sensitivity and specificity and are not used alone for cancer screening. Circulating cell-free tumour DNA (ctDNA) was found in levels ≥ 0.75% in advanced metastatic breast cancer and has a sensitivity of over 90% and specificity over 99% and is a promising biomarker (27). The miRNAs (small regulatory RNA molecules) are upregulated in the serum of breast cancer patients and could differentiate diseased patients from healthy controls. Many studies have shown the effectiveness of miRNAs in distinguishing breast cancer from healthy control and also to differentiate malignant lesions from benign lesions (28). But a panel of circulating miRNAs that is ready to be used in a clinical setting is still unavailable. Extracellular Vesicles (EV) comprise microparticles, microvesicles, prostasomes, endosomes, and tolerosomes and are secreted from normal as well as cancer cells. Although, EVs are not specific for cancer diagnosis, their elevated levels in breast cancer and their ability to mirror the origin and tumour state brought them attention as breast cancer biomarkers (29). Phospholipids like Phosphatidylethanolamine (PE), Phosphatidylcholine (PC), and sphingomyelin are present in abundant quantities in the cell membrane and their metabolism is increased in cancer tissues. When urine samples of breast cancer patients were analyzed by nanoflow liquid chromatography/electrospray ionization tandem mass spectrometry, the concentrations of PCs and PEs increased by 44% and 71% respectively when compared with that of healthy controls (30). Additionally, a panel of 11 upregulated proteins was also identified in the urine samples of breast cancer patients as mentioned in (Table/Fig 3), which were stage-specific (31). Nipple Aspirate Fluid (NAF) is another rich source of breast cancer biomarkers. Apart from a high concentration of proteins, carbohydrates, and metabolites, it also contains exfoliated breast epithelial cells from which breast cancer originates. The Thomsen-Freiden reich (TF) antigen and its precursor Tn antigen are expressed in higher amounts in NAF of breast cancer patients and the TF concentrations could differentiate precancerous and cancerous lesions from benign disease (32). Saliva is an easily accessible body fluid and has elevated levels of salivary fluid protein biomarkers in breast cancer as measured by ELISA. Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF) and Carcinoembryonic Antigen (CEA) levels were significantly increased in breast cancer and saliva can serve as a useful tool to supplement the current methods of breast cancer detection (28).

Activated leucocyte cell adhesion molecule is one such non invasive biomarker that detects the metastasis and prognosis of breast cancer with high sensitivity (24). In recent years, extensive research is being done on ALCAM about its usefulness as a potential non invasive biomarker of breast cancer. ALCAM is associated with tumour growth and metastasis and also protects the breast cancer cells from cell death and autophagy (33). It is gaining more attention because of its extremely high levels in breast cancer. Apart from being simple, quick, and selective the detection of ALCAM is also cost-effective and this has been a breakthrough in early breast cancer screening and prognosis assessment (34).

Activated Leucocyte Cell Adhesion Molecule (ALCAM)

Adhesion molecules are classified into immunoglobulins, cadherins, selectins, integrins, and mucins and they can involve in tumour cell-tumour cell adhesion, tumour cell-matrix adhesion, and tumour cell-endothelial adhesion. These adhesions play a role in primary tumour formation and tumour metastasis and can be upregulated or downregulated during this process. Adhesion molecules influence cellular growth, differentiation, and junction formation and can contribute to unrestrained cell growth (19),(35).

ALCAM is a glycoprotein of the immunoglobulin superfamily of adhesion molecules and is mapped to chromosome 3q13 (8). Research has revealed that cancer biomarkers are not specific and sensitive in detecting early disease stages. ALCAM which is a transmembrane glycoprotein receptor has five extracellular immunoglobulin-like domains that can mediate cell-cell clustering employing homophilic (ALCAM-ALCAM) and heterophilic (ALCAM-CD166) interaction (11). ALCAM is involved in the maintenance of tissue architecture, immune response, and tumour progression.

The sALCAM is soluble form of ALCAM that is formed by ADAM17/TACE metalloprotease activity and its levels were found to increase in certain types of cancer. There are also shreds of evidence of expression of ALCAM in colon cancer and in metastatic melanoma where they are responsible for local cell spread to tissue invasion (10),(12). There were contradictory reports about the expression of ALCAM in breast cancer. But recent studies have proved that ALCAM is expressed in extremely high levels in breast cancer and is associated with disease prognosis. The high membranous expression causes weakened adherence of the malignant cells and promotes tumour development (24). Zhou et al., in their study also demonstrated that ALCAM is associated with tumour progression and metastasis. A low ALCAM expression can cause apoptosis and autophagy of the cancer cells and its presence protects the breast cancer cells against these two programmed cell death processes (36).

Studies have assessed that ALCAM shows a pattern in its expression according to the grade, stage, and invasive nature of the tumour, and the prognostic value varies depending on the type of cancer. ALCAM may be upregulated in the early stages of prostate cancer but down-regulated with tumour progression. On the contrary, in melanoma, oesophageal carcinoma, and breast carcinoma, the levels of ALCAM expression are directly related to invasiveness and metastasis (10),(37),(38). Many controversies still exist in the study results of breast cancer. The expression of ALCAM has been detected in the breast cancer cell lines of MCF10A, MCF10AT, MCF10CA Cl-A, MCF10CA Cl-D, and MDA-MB-23146 according to the unpublished results of study by Ofori-Acquah SF and King JA (10). The study finding also showed that the cell lines MCF-7 and MDA-MB-435 had very weak ALCAM expressions (10). The study also demonstrated the first analysis of ALCAM mRNA expression in breast cancer. Low levels of ALCAM m RNA correlated with nodal metastasis, high-grade tumour, and poor clinical outcomes in a study of 120 primary breast carcinomas where ALCAM was measured by PCR and analysed concerning clinical data from a six year follow-up period (10). (Table/Fig 5) shows the levels of ALCAM expressions among different types of carcinomas.

Splice Variants of ALCAM

ALCAM has nine identified splice variants, out of which only two isoforms have been confirmed on both mRNA and protein levels. ALCAM-Iso1is composed of all 15 coding exons and ALCAM-Iso2 lacks exon 13, which corresponds to 13 amino acids in the stalk region of the protein. The functional and biochemical differences between the two isoforms have not yet been explored (47). The variant ?N-ALCAM is caused by a deletion mutation and disturbs the ligand-receptor binding function and cognitive properties of ALCAM. It mostly conserves the oligomerisation properties and the ectopic expression of this variant is involved in the intercellular networks of ALCAM. An overexpression of ?N-ALCAM worsens the invasive behaviour of the cells by interfering with the homophilic interactions of endogenous ALCAMs (48).

Similarly, sALCAM is a shortened form of ALCAM transcript in endothelial cells that consists of the first three axons and encoding the NH2- terminal sequence with the first variable domain. sALCAM was first isolated by Ikeda et al and his study reported that the expression of sALCAM and ALCAMs in Human Microvascular Endothelial Cells (HMVEC) is differently regulated by Tumor Necrosis Factor Alpha (TNF-α) stimulation. sALCAM can also independently affect the cell migration process (48). Yet, another form released from the ectodomain of ALCAM structure through proteolytic cleavage is so ALCAM. The actual role of these molecules is yet to be discovered, but they serve as molecular buffers capable of neutralising excess ligands.

Comparative Studies on ALCAM

Several studies have been conducted so far about the effectiveness of ALCAM in breast cancer detection and prognosis assessment. The expression of ALCAM in advanced and metastatic disease directly and positively correlated with a poor prognostic value. The results were also specific when compared to the other biomarkers. Witzela I et al., conducted a cohort study among 157 primary breast cancer patients and compared the results with ALCAM protein and mRNA expression in the tumour tissue of those patients using cDNA arrays and Western blot analysis. The association between ALCAM levels and clinicopathological parameters and survival data was also assessed. In univariate analysis, high sALCAM levels were significantly associated with shorter Disease-free Survival (DFS). Also, 36% of the patients have disease recurrence and 25% of the patients died in a median follow-up of 87 months (49).

Ihnen M et al., in their study in 1997-2005 among 25 tissue samples of primary breast cancer and 84 samples of the advanced disease reported found that ALCAM staining was found in 24 out of 25 primary breast cancer patients. But in metastatic samples (except two), no ALCAM staining was seen (50). This finding is similar to the study results of Jezierska A et al., who reasoned that aggressive breast cancer correlates with low ALCAM values as the malignant cells could dissolve out the primary tumour and spread easily due to the absence of connecting adhesion molecule (33). Kulasingam V et al., measured the concentration of ALCAM in serum using a highly sensitive and specific non-competitive “sandwich-type” ELISA among 150 patients with breast cancer. Their study results showed evidence that serum ALCAM concentration has potential utility as a diagnostic tool. In addition, the combination of ALCAM with CA15-3 improved the diagnostic sensitivity and an elevated ALCAM level was associated with increasing age (51).

Fawziah S, in his study compared the effects of ALCAM, CA 15-3, and CEA and their results revealed that the p-value of ALCAM was highly significant in grade II and grade III tumours by 90% and 127% respectively, while CA15-3 was significant by 40%, 72%, and CEA was significant by 33%, 156%, respectively. They demonstrated ALCAM as the most sensitive and specific biomarker in breast cancer detection when compared to CA15-3 and CEA (52). Ajeed Am et al., in their study compared the expression of ALCAM, CEA, and CA15-3 in benign and malignant breast carcinoma and their results revealed that the p-value between patients with benign tumour and control was 0.015, p-value between malignant tumour and control was <0.001, p-value between patients with malignant tumours and benign tumours was 0.044 and p-value among all studied group by Analysis of Variance (ANOVA) was <0.001 (53). The ROC curve results revealed that CEA and CA15-3 and also the combination between them had low AUC, sensitivity, and specificity values whereas ALCAM showed higher AUC values with acceptable sensitivity and specificity in patients with a malignant tumour when compared with benign tumours (40). Lal N et al., in their study report in 2016 stated that a positive association between serum ALCAM levels and disease grading was observed. The median ALCAM levels in grade I patients was 91.350 and in grade II it was 215.743 in their study. The median serum ALCAM levels were highest in grade III 490.773 (p-value=0.005). There was no significant difference in the levels of serum and salivary CA-15-3 across the three grades. In regards to the correlation with morphological parameters and grade, the values of serum ALCAM significantly correlated with the nuclear size and thereby, the histopathological grade. The values of sALCAM increased proportionately with higher grades (54). The study finding results of Lal N et al., were similar to that of Mohammed AS et al., findings. This study author compared the expression of ALCAM, CEA, and CA15-3 in breast cancer women and concluded that the serum ALCAM may represent a diagnostic biomarker for early detection of breast cancer (55). (Table/Fig 6) shows a list of studies done on ALCAM expression in breast cancer patients.

It was believed that no single cancer biomarker can provide all necessary information for optimal cancer diagnosis and the focus has been on the identification of biomarkers that can be used in combination. This review provides evidence that serum ALCAM displays a higher diagnostic sensitivity for breast cancer detection when compared with the other tumour markers.

ALCAM is expressed at certain levels in melanoma, prostate, and bladder cancer but shows 95% specificity to breast cancer detection. These findings represent ALCAM as a single potential candidate for breast cancer detection and prognosis assessment.

Conclusion

A lot of invasive and non invasive biomarkers for early breast cancer detection have been described in the last few decades to overcome the limitations of mammogram screening and other modalities of tumour detection. Few studies suggest that level of ALCAM expression is more when compared to CA15-3 and CEA. Studies suggest that decreased ALCAM expression is an indication for a bad prognosis of malignancy in few cancers but elevated levels of ALCAM were seen found in breast carcinoma. The proteomic nature of ALCAM can facilitate its expression in other biological fluids like urine and saliva. But, many studies researched the expression of ALCAM in both breast tumour tissue and serum of breast cancer patients but no studies were conducted on non invasive methods of ALCAM expression in breast cancer patients. Despite limitations, serum ALCAM is a promising biomarker for early breast cancer detection and exhibits higher specificity and sensitivity. Further extensive studies focussing on the detection methods of ALCAM and comparing its effectiveness with other cancer biomarkers would prompt for an in-depth understanding of its exclusivity in breast cancer detection.

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DOI and Others

DOI: 10.7860/JCDR/2023/59550.17359

Date of Submission: Aug 08, 2022
Date of Peer Review: Oct 03, 2022
Date of Acceptance: Nov 16, 2022
Date of Publishing: Jan 01, 2023

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No

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