What is Ki-67?
The Ki-67 antigen is widely recognized as a marker of cellular proliferation, particularly associated with ribosomal RNA, which is essential for correct ribosome production and protein synthesis. Ki-67 is present during the active phases of the cell cycle, including interphase and mitosis, where it supports ribosomal RNA synthesis. Inactivation of Ki-67 leads to the inhibition of this process.
Interphase is the longest phase of the cell cycle, during which the cell grows, synthesizes proteins, replicates DNA, and prepares for mitosis, the next phase of the cycle. During interphase, Ki-67 helps ensure the proper distribution of heterochromatin—a tightly packed and less active form of DNA—and its interactions with the nucleolus, a cellular structure involved in ribosome production.
Mitosis is a shorter phase during which the cell’s nuclear material is divided into two identical sets, followed by the division of the cytoplasm to form two new cells. During mitosis, Ki-67 participates in the formation of a protective sheath around condensed chromosomes, known as the perichromosomal layer (PCL). As part of the PCL, Ki-67 ensures proper chromosome segregation during cell division, preventing the chromosomes from clumping together.1
Ki-67 antigen test
Since Ki-67 is present in human cells only during the active phases of the cell cycle and its levels strongly correlate with progression through the S phase, it is widely used to assess tumor grade, which describes the pace of tumor growth. Generally, higher Ki-67 levels indicate more aggressive tumors. Additionally, Ki-67 is also used for cancer monitoring and evaluating the response to therapy.2
The Ki-67 test is performed on tumor tissue, requiring a sample that can be collected through endoscopic, surgical, or needle biopsy, depending on the tumor’s location. This sample is then stained with an antibody that binds to Ki-67, and the percentage of cells stained positive for this protein is calculated. This number is known as the Ki-67 index, Ki-67 score or Ki-67 proliferation index.3
The definition of the Ki-67 normal range varies depending on the laboratory and healthcare provider, but it is primarily determined by the regenerative capacity of the tissue.
For example, healthy intestinal lining tissues, which have a naturally high regenerative capacity, may show a higher Ki-67 score, potentially reaching close to 10%. In contrast, organs with much slower turnover, such as the brain and heart, typically have a Ki-67 score below 1% in healthy tissues. A higher Ki-67 score in these slower-turnover tissues can indicate medium-grade tumor development.
Factors increasing Ki-67
Elevated levels of Ki-67 are associated with active tumor growth in many cancers, with particularly clear correlations in:
- Breast cancer, especially in estrogen receptor-positive/HER2-negative cases;
- Prostate cancer;
- Thyroid cancer;
- Brain tumors;
- Bladder cancer;
- Lung cancer;
- Gastrointestinal cancers;
- Neuroendocrine tumors.
Thus, the Ki-67 breast cancer marker has a potential application in assessing other oncological conditions.
However, increased Ki-67 levels can also occur naturally in individuals with wounds and inflammatory conditions, as the body requires increased cell proliferation to heal tissue injuries. Benign tumors can also show a higher Ki-67 index, as can other health conditions such as benign endometrial hyperplasia and prostatic hyperplasia. Hormonal imbalances and treatments may also affect the Ki-67 score.
References:
- Sun X Kaufman PD. “Ki-67: more than a proliferation marker.” Chromosoma. 2018. 127(2):175-186.
https://pubmed.ncbi.nlm.nih.gov/29322240/#:~:text=In%20this%20structure,%20Ki-67%20acts%20to%20prevent%20aggregation%20of%20mitotic - Razmi M et al. “The Prognostic Importance of Ki-67 in Gastrointestinal Carcinomas: A Meta-analysis and Multi-omics Approach.” Journal of Gastrointestinal Cancer. 2024. 55(599-624).
https://link.springer.com/article/10.1007/s12029-024-01022-w - “Ki-67 proliferation index.” National Cancer Institute.
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ki-67-proliferation-index