The expression of the human Ki-67 protein is strictly associated with cell proliferation. During interphase, the antigen can be exclusively detected within the nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. The fact that the Ki-67 protein is present during all active phases of the cell cycle (G(1), S, G(2), and mitosis), but is absent from resting cells (G(0)), makes it an excellent marker for determining the so-called growth fraction of a given cell population. In the first part of this study, the term proliferation marker is discussed and examples of the applications of anti-Ki-67 protein antibodies in diagnostics of human tumors are given. The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of the disease. The best-studied examples in this context are carcinomas of the prostate and the breast. For these types of tumors, the prognostic value for survival and tumor recurrence has repeatedly been proven in uni- and multivariate analysis. The preparation of new monoclonal antibodies that react with the Ki-67 equivalent protein from rodents now extends the use of the Ki-67 protein as a proliferation marker to laboratory animals that are routinely used in basic research. The second part of this review focuses on the biology of the Ki-67 protein. Our current knowledge of the Ki-67 gene and protein structure, mRNA splicing, expression, and cellular localization during the cell-division cycle is summarized and discussed. Although the Ki-67 protein is well characterized on the molecular level and extensively used as a proliferation marker, the functional significance still remains unclear. There are indications, however, that Ki-67 protein expression is an absolute requirement for progression through the cell-division cycle.

The Ki‐67 protein: From the known and the unknown

Pathology and genetics of tumours of the urinary system and male genital organs

BACKGROUND AND AIMS Controversy surrounds the risk of colorectal cancer (CRC) in ulcerative colitis (UC). Many studies have investigated this risk and reported widely varying rates. METHODS A literature search using Medline with the explosion of references identified 194 studies. Of these, 116 met our inclusion criteria from which the number of patients and cancers detected could be extracted. Overall pooled estimates, with 95% confidence intervals (CI), of cancer prevalence and incidence were obtained using a random effects model on either the log odds or log incidence scale, as appropriate. RESULTS The overall prevalence of CRC in any UC patient, based on 116 studies, was estimated to be 3.7% (95% CI 3.2–4.2%). Of the 116 studies, 41 reported colitis duration. From these the overall incidence rate was 3/1000 person years duration (pyd), (95% CI 2/1000 to 4/1000). The overall incidence rate for any child was 6/1000 pyd (95% CI 3/1000 to 13/1000). Of the 41 studies, 19 reported results stratified into 10 year intervals of disease duration. For the first 10 years the incidence rate was 2/1000 pyd (95% CI 1/1000 to 2/1000), for the second decade the incidence rate was estimated to be 7/1000 pyd (95% CI 4/1000 to 12/1000), and in the third decade the incidence rate was 12/1000 pyd (95% CI 7/1000 to 19/1000). These incidence rates corresponded to cumulative probabilities of 2% by 10 years, 8% by 20 years, and 18% by 30 years. The worldwide cancer incidence rates varied geographically, being 5/1000 pyd in the USA, 4/1000 pyd in the UK, and 2/1000 pyd in Scandinavia and other countries. Over time the cancer risk has increased since 1955 but this finding was not significant (p=0.8). CONCLUSIONS Using new meta-analysis techniques we determined the risk of CRC in UC by decade of disease and defined the risk in pancolitics and children. We found a non-significant increase in risk over time and estimated how risk varies with geography.

https://gut.bmj.com/content/gutjnl/48/4/526.full.pdf

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Neoplasms are microcosms of evolution. Within a neoplasm, a mosaic of mutant cells compete for space and resources, evade predation by the immune system and can even cooperate to disperse and colonize new organs. The evolution of neoplastic cells explains both why we get cancer and why it has been so difficult to cure. The tools of evolutionary biology and ecology are providing new insights into neoplastic progression and the clinical control of cancer.

Cancer as an evolutionary and ecological process.

The athymic (nude) mouse is a useful model for studying the biology and response to therapies of human tumors in vivo. A survey of recent literature revealed the use of 19 different formulas for determining the size of subcutaneous tumors grown as xenografts in nude mice (2 for determining tumor area, 3 for tumor diameter, and 14 for calculating tumor volume). We compared the volumes, areas, and diameters predicted by each of the 19 formulas with the actual weights of 50 tumors ranging from 0.46 to 22.0 g established in nude mice as xenografts from human cell lines. In addition to determining how well each formula predicted relative tumor size, we analyzed how well each formula estimated actual tumor mass. The ellipsoid volume formulas (π/6 x L x W x H and 1/2 x L x W x H) were best for estimating tumor mass (r=0.93), whereas measurements of diameter correlated poorly with tumor mass (r<0.66). Although determination of tumor area correlated well with tumor mass in small tumors (r=0.89), correlations of area with tumor mass for large tumors were poor (r=0.41). We conclude that determination of the ellipsoid volume from measurements of three axes consistently yields the most accurate estimations of both relative and actual tumor mass.

Determination of subcutaneous tumor size in athymic (nude) mice

Colonoscopic surveillance in long-standing total ulcerative colitis—A 15-year follow-up study

Flow cytometry allows the cellular DNA content of tumors to be measured in a large number of cells with a high degree of accuracy. In addition to the degree of ploidy, reflecting the total number of chromosomes or the stem line of the tumor, the proportions of cells in the various parts of the cell cycle can be determined. The high speed of the method fulfils one prerequisite for application in clinical use. This article reviews the accumulated experience of flow cytometry on cell material of tumors of the genito-urinary tract demonstrating that carcinomas of the bladder, the prostate, and renal cell carcinomas can be further subdivided according to ploidy characteristics and proportions of s-phase cells. Follow-up shows the prognostic significances of these tumor properties. Flow cytometry can therefore be expected to become a valuable adjunct to clinical staging and morphologic grading in the assessment of the malignancy potential of genito-urinary neoplasms.

Flow cytometry in assessing the clinical aggressiveness of genito-urinary neoplasms

The cellular DNA content in colorectal biopsies from 51 patients with chronic ulcerative colitis has been studied with flow-cytometric technique. The DNA pattern has been related to the duration of the disease, and to histopathology. Aneuploid cell lines were found in eight patients, two of which had histopathologically verified malignancies. Aneuploid cell lines were found in 2% of biopsies from mucosa classified as normal, in 10% of biopsies with inflammation, hyperplasia or atrophy, in 25% of polyps and in biopsies with dysplasia and in seven of eight biopsies from adenocarcinomas. Four of 27 cases with 11 to 20 years duration of disease, and 4 of 10 with more than 20 years disease, had aneuploid cell lines. Combined with colonoscopy the flow-cytometric technique can routinely be used in the follow-up of patients with ulcerative colitis in screening for malignant cell lines.

Early detection of malignancy in ulcerative colitis. A flow-cytometric DNA study.

https://www.gastrojournal.org/article/S0016-5085(97)70029-5/pdf

Neoplastic Transformation of the Pelvic Pouch Mucosa in Patients With Ulcerative Colitis

229 patients with Grade 1-2 tumours (WHO), all category Ta or T1 (UICC) and surgically treated, were followed clinically and by flowcytofluorometric DNA-analysis (FCM). The tumours were characterised by their DNA profile. 175 cases were found to be diploid and fifty-four cases showed aneuploidy. The mean follow-up time with continuous FCM analysis was 2.6 years. During this period 19 patients showed tumour progression and 11 of these patients died. No progressive cases were found among 175 patients with repeatedly diploid DNA patterns. Thus tumour progression was exclusively linked to an aneuploid DNA pattern. In these case the degree of ploidy determined the frequency of progression: while 50% of the cases with triploid--hypotetraploid DNA pattern showed progression, only 10% of tumours with a tetraploid amount of DNA were found to be progressive. The degree of ploidy in 33 cases with recurrent aneuploid tumours was in general found to be constant. A fairly high degree of consistency was also found in the number of cells in S-phase, expressing proliferative properties. This indicates that superficial bladder tumours can be well characterised by their DNA profiles, that is the degree of ploidy and the proliferation pattern.

Bernhard Tribukait

Papers

Colonoscopic surveillance in long-standing total ulcerative colitis—A 15-year follow-up study

Flow cytometry in assessing the clinical aggressiveness of genito-urinary neoplasms

Early detection of malignancy in ulcerative colitis. A flow-cytometric DNA study.

Neoplastic Transformation of the Pelvic Pouch Mucosa in Patients With Ulcerative Colitis

DNA profile and tumour progression in patients with superficial bladder tumours.