Cell proliferation in breast tumours: Analysis of histological parameters Ki67 and PCNA expression

In last decades, the basic, clinical, and translational research efforts have been directed to the identification of standard biomarkers associated with the degree of malignancy. There is an increasingly public health concern for earlier detection of cancer development at stages in which successful treatments can be achieved. To meet this urgent clinical demand, early stage cancer biomarkers supported by reliable and robust experimental data that can be readily applicable in the clinical practice, are required. In the current standard protocols, when one or two of the canonical proliferating index biomarkers are analyzed, contradictory results are frequently reached leading to incorrect cancer diagnostic and unsuccessful therapies. Therefore, the identification of other cellular characteristics or signatures present in the tumor cells either alone or in combination with the well-established proliferation markers emerge as an alternative strategy in the improvement of cancer diagnosis and treatment. Because it is well known that several pathways and processes are altered in tumor cells, the concept of "single marker" in cancer results incorrect. Therefore, this review aims to analyze and discuss the proposal that the molecular profile of different genes or proteins in different altered tumor pathways must be established to provide a better global clinical pattern for cancer detection and prognosis.

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“…However, poor correlation with other proliferation index such as Ki-67 expression and mitotic index has been observed [Sullivan et al, 1993].…”

Section: Proliferating Cell Nuclear Antigen (Pcna)mentioning

confidence: 99%

Multi-biomarker pattern for tumor identification and prognosis

et al. 2011

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“…Cells that showed specific nuclear staining were scored as positive and the Ki67 labelling index was expressed as the percentage of the total number of tumour cells that stain positive; this equates to the growth fraction of the tumour. Higher grade cancers have higher Ki67 indices – one study found mean scores of 9% in grade I tumours, 14% in grade II and 26% in grade III [23]. The Ki67 index correlates significantly with estimates of the mitotic index [24] and SPF by flow cytometry [13,25,26], although some of the published correlation coefficients are modest (r = 0.42 [13], r = 0.22 [26]).…”

Section: Nuclear Antigensmentioning

confidence: 99%

Measuring proliferation in breast cancer: practicalities and applications

2006

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Various methods are available for the measurement of proliferation rates in tumours, including mitotic counts, estimation of the fraction of cells in S-phase of the cell cycle and immunohistochemistry of proliferation-associated antigens. The evidence, advantages and disadvantages for each of these methods along with other novel approaches is reviewed in relation to breast cancer. The potential clinical applications of proliferative indices are discussed, including their use as prognostic indicators and predictors of response to systemic therapy. IntroductionThe development and continued growth of cancers involves altered rates of cell proliferation. In early breast cancer, measurement of proliferation can be used in conjunction with tumour size, grade, nodal status and steroid receptor status as a prognostic indicator [1,2]. Proliferation rates can provide useful information on prognosis and aggressiveness of individual cancers and can be used to guide treatment protocols in clinical practice. Adjuvant chemotherapy has been shown to improve survival in patients with breast cancer, but has potentially serious side effects. The potential of prognostic factors is to determine which patients are at higher risk of recurrence such that patients who stand to benefit more from adjuvant treatment can be identified. In the future, changes in proliferation rates during or after systemic therapy may be utilized as predictors of response and allow further tailoring of therapy. Information on proliferation rates is also necessary for the development of therapeutic agents, some of which may be targeted directly at specific points in the cell division pathway.Various techniques have been developed to evaluate and quantify proliferation rates in the laboratory. Mitotic count estimates are widely used as a simple measure of cellular proliferation and are often incorporated into tumour grading systems [3]. Other methods have been developed, such as the detection of cells undergoing DNA synthesis using assays for thymidine uptake [4], flow cytometry to estimate the percentage of cells in S phase of the cell cycle or the detection of antigens associated with proliferation. This review will discuss current and developmental methods for assessing proliferation and the potential applications of such knowledge in the treatment of breast cancer. Table 1 summarises these methods and highlights their individual advantages and limitations. Mitotic indexCellular proliferation involves several defined phases. Cells in the resting (G0) phase are stimulated to enter the active cycle at the first gap (G1) phase. During this period of time, the cell prepares for DNA synthesis (the S phase), which is followed by a second phase of relative inactivity (G2) and preparation for the separation of the chromatids in the mitotic (M) phase. Cells can then recycle by entering the G1 phase or return to the resting G0 phase. Proliferation was first measured by counting mitotic bodies on paraffin-embedded tumour specimens stained using haematoxylin-eo...

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“…1A, S-phase cells in HCT116 xenografts can be observed nearer to blood vessels, whereas quiescent cells predominate in areas further from vessels. Despite uncontrolled proliferation being a hallmark of cancer, human tumors often exhibit proliferative indices as low as 5% to 10% (14). Even micrometastases of a quarter of a millimeter in size will possess regions of hypoxia and nutrient deprivation leading to tumor cell quiescence (10,15).…”

Section: Introductionmentioning

confidence: 99%

Targeting Quiescent Tumor Cells via Oxygen and IGF-I Supplementation

Kyle¹,

Baker²,

Minchinton³

2012

Cancer Research

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Conventional chemotherapy targets proliferating cancer cells, but most cells in solid tumors are not in a proliferative state. Thus, strategies to enable conventional chemotherapy to target noncycling cells may greatly increase tumor responsiveness. In this study, we used a 3-dimensional tissue culture system to assay diffusible factors that can limit proliferation in the context of the tumor microenvironment, with the goal of identifying targets to heighten proliferative capacity in this setting. We found that supraphysiologic levels of insulin or insulin-like growth factor I (IGF-I) in combination with oxygen supplementation were sufficient to initiate proliferation of quiescence cells in this system. At maximal induction with IGF-I, net tissue proliferation increased 3-to 4-fold in the system such that chemotherapy could trigger a 3-to 6-fold increase in cytotoxicity, compared with control conditions. These effects were confirmed in vivo in colon cancer xenograft models with demonstrations that IGF-I receptor stimulation was sufficient to generate a 45% increase in tumor cell proliferation, along with a 25% to 50% increase in chemotherapy-induced tumor growth delay. Although oxygen was a dominant factor limiting in vitro tumor cell proliferation, we found that oxygen supplementation via pure oxygen breathing at 1 or 2 atmospheres pressure (mimicking hyperbaric therapy) did not decrease hypoxia in the tumor xenograft mouse model and was insufficient to increase tumor proliferation. Thus, our findings pointed to IGF-I receptor stimulation as a rational strategy to successfully increase tumor responsiveness to cytotoxic chemotherapy.

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Cell proliferation in breast tumours: Analysis of histological parameters Ki67 and PCNA expression

Cited by 29 publications

References 21 publications

Multi-biomarker pattern for tumor identification and prognosis

Multi-biomarker pattern for tumor identification and prognosis

Measuring proliferation in breast cancer: practicalities and applications

Targeting Quiescent Tumor Cells via Oxygen and IGF-I Supplementation

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