Proliferative index

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Proliferation, as one of the hallmarks and most fundamental biological processes in tumors, [1] is associated with tumor progression, response to therapy, and cancer patient survival. [2] Consequently, the evaluation of a tumor proliferative index (or growth fraction) has clinical significance in characterizing many solid tumors and hematologic malignancies. [3] This has led investigators to develop different technologies to evaluate the proliferation index in tumor samples. The most commonly used methods in evaluating a proliferative index include mitotic indexing, thymidine-labeling index, bromodeoxyuridine assay, the determination of fraction of cells in various phases of cell cycle, and the immunohistochemical evaluation of cell cycle-associated proteins.

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Mitotic index (also called mitotic count)

Mitosis in a neuroendocrine tumor. Mitosis in a neuroendocrine tumor.jpg
Mitosis in a neuroendocrine tumor.

Mitotic indexing is the oldest method of assessing proliferation and is determined by counting the number of mitotic figures (cells undergoing mitosis) through a light microscope on H&E stained sections. It is usually expressed as the number of cells per microscopic field. Cells in the mitotic phase are identified by the typical appearance of their chromosomes in the cell during the mitotic phase of the cell cycle. [4] Usually the number of mitotic figures is expressed as the total number in a defined number of high power fields, such as 10 mitoses in 10 high power fields. Since the field of vision area can vary considerably between different microscopes, the exact area of the high power fields should be defined in order to compare results from different studies. Accordingly, one of the main problems of counting mitosis has been the reproducibility. Thus, the need for standardized methodology and strict protocols is important to achieve reproducible results. [5] Automated image alalysis using deep learning-based algorithms has been proposed as a promising tool to assist pathologists and thereby improve reproducibility and accuracy. [6]

Thymidine-labeling index

Thymidine-labeling indexing is determined by counting the number of tumor nuclei labeled on autoradiographed sections after incubating the tumor cells with thymidine. Rapidly proliferating cells readily update more radiolabeled Thymidine, which produces darker spots on the autoradiograph film. [7]

Bromodeoxyuridine assay

A bromodeoxyuridine assay, similar to thymidine-labeling indexing, incubates cells with radiolabeled bromodeoxyuridine, which is taken up at a greater rate by proliferating cells, and then uses a film to image the distribution of radiolabeled bromodeoxyuridine in cells.

S-phase fraction evaluation

Evaluating DNA histograms through flow cytometry provides an estimate of the fractions of cells within each of the phases in the cell cycle. Cell nuclei are stained with a DNA binding stain and the amount of staining is measured from the histogram. [8] The fractions of cells within the different cell cycle phases (G0/G1, S and G2/M compartments) can then be calculated from the histogram by computerized cell cycle analysis.

Immunohistochemical evaluation

The immunohistochemical detection of proliferation related proteins such as Ki-67 and proliferating cell nuclear antigen is a commonly used method to determine the proliferation index. Ki-67 is a nuclear antigen expressed in proliferating cells that is coded by the MKI67 gene on chromosome 10, and is expressed during the GI, S, G2, and M phases of the cell cycle. Cells are then stained with a Ki-67 antibody, and the number of stained nuclei is then expressed as a percentage of total tumor cells. It is recommended to count at least 500 tumor cells in the highest labeled area. The Ki-67 score closely correlates with other proliferation markers, and has been shown to have prognostic and predictive value for many different tumor types. [9] Similarly, proliferating cell nuclear antigen (PCNA) is a protein associated with cell proliferation that is upregulated in proliferating cells, making it another useful antigen for immunostaining. [10] It is associated with DNA polymerase alpha, which is expressed throughout the phases of the cell cycle. The expression of PCNA also correlates well with other proliferation markers such as mitotic count, S-phase fraction and Ki-67 staining.

Diagnostic role of proliferation index

The various methods of characterizing the proliferation index have found roles in both the diagnostic and prognostic evaluation of tumors. For instances, the number of mitotic cells is used to classify tumors. In general, a high proliferation index suggests malignancy and high-grade tumors. [11] Among solid tumors, the clinical significance of the proliferation index on breast cancer has been extensively studied. Mitotic counting has also been shown in multiple studies to have prognostic value in breast cancer, where a lower count of mitotic cells correlates with a more favorable outcome, and thus has been incorporated into part of the histological grading system. The Ki-67 labelling index has also been found to have prognostic significance where in many clinical practice guidelines, evaluation of Ki-67 in newly diagnosed invasive breast carcinomas is recommended. [12] Additionally, the tumor proliferation index has been used to predict the response to systemic chemotherapies in patients who are receiving neoadjuvant systemic therapy where patients who have tumors with high tumor proliferative index respond better to systemic cytotoxic therapies than those who have tumors with a low tumor proliferative index. [13]

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Mitosis</span> Process in which chromosomes are replicated and separated into two new identical nuclei

Mitosis is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the total number of chromosomes is maintained. Mitosis is preceded by the S phase of interphase and is followed by telophase and cytokinesis, which divide the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis altogether define the mitotic phase of a cell cycle—the division of the mother cell into two daughter cells genetically identical to each other.

G<sub>1</sub> phase First growth phase in the eukaryotic cell cycle

The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes mRNA and proteins in preparation for subsequent steps leading to mitosis. G1 phase ends when the cell moves into the S phase of interphase. Around 30 to 40 percent of cell cycle time is spent in the G1 phase.

<span class="mw-page-title-main">Cell growth</span> Increase of the total mass of the cancer cells

Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis is greater than the overall rate of cellular degradation.

<span class="mw-page-title-main">Thymidine kinase</span> Enzyme found in most living cells

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a mitogen is that it triggers signal transduction pathways involving mitogen-activated protein kinase (MAPK), leading to mitosis.

Mitotic index is defined as the ratio between the number of a population's cells undergoing mitosis to its total number of cells.

<span class="mw-page-title-main">Bromodeoxyuridine</span> Compound commonly used to detect proliferating cells

Bromodeoxyuridine is a synthetic nucleoside analogue with a chemical structure similar to thymidine. BrdU is commonly used to study cell proliferation in living tissues and has been studied as a radiosensitizer and diagnostic tool in people with cancer.

<span class="mw-page-title-main">Cyclin B</span> Protein family

Cyclin B is a member of the cyclin family. Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B. The complex of Cdk and cyclin B is called maturation promoting factor or mitosis promoting factor (MPF).

<span class="mw-page-title-main">Cyclin E</span> Member of the cyclin family

Cyclin E is a member of the cyclin family.

<span class="mw-page-title-main">Aurora kinase A</span> Protein-coding gene in the species Homo sapiens

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.

<span class="mw-page-title-main">Ki-67 (protein)</span> Mammalian protein found in humans

Antigen Kiel 67, also known as Ki-67 or MKI67, is a protein that in humans is encoded by the MKI67 gene.

Cell synchronization is a process by which cells in a culture at different stages of the cell cycle are brought to the same phase. Cell synchrony is a vital process in the study of cells progressing through the cell cycle as it allows population-wide data to be collected rather than relying solely on single-cell experiments. The types of synchronization are broadly categorized into two groups; physical fractionization and chemical blockade.

<span class="mw-page-title-main">CDKN1B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

<span class="mw-page-title-main">Cyclin B1</span> Protein-coding gene in the species Homo sapiens

G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene.

<span class="mw-page-title-main">Thymidine kinase 1</span> Human protein and coding gene

Thymidine kinase 1, soluble, is a human thymidine kinase.

<span class="mw-page-title-main">Basal-like carcinoma</span> Breast cancer subtype

The basal-like carcinoma is a recently proposed subtype of breast cancer defined by its gene expression and protein expression profile.

<span class="mw-page-title-main">STIL</span> Protein-coding gene in the species Homo sapiens

SCL-interrupting locus protein is a protein that in humans is encoded by the STIL gene. STIL is present in many different cell types and is essential for centriole biogenesis. This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint.

<span class="mw-page-title-main">Mitotic catastrophe</span> Mechanism of cell death

Mitotic catastrophe has been defined as either a cellular mechanism to prevent potentially cancerous cells from proliferating or as a mode of cellular death that occurs following improper cell cycle progression or entrance. Mitotic catastrophe can be induced by prolonged activation of the spindle assembly checkpoint, errors in mitosis, or DNA damage and operates to prevent genomic instability. It is a mechanism that is being researched as a potential therapeutic target in cancers, and numerous approved therapeutics induce mitotic catastrophe.

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21 that catalyzes the reaction:

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PD-icon.svg This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.