Ki67 is a graded rather than a binary marker of proliferation vs. quiescence
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ABSTRACT:
SUBMITTER: Sabrina Spencer
PROVIDER: S-BSST167 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Ki67 staining is widely used as a proliferation indicator in the clinic, despite poor understanding of this protein's function or dynamics. Here, we track Ki67 levels under endogenous control in single cells over time and find that Ki67 accumulation occurs only during S, G2, and M phases. Ki67 is degraded continuously in G1 and G0 phases, regardless of the cause of entry into G0/quiescence. Consequently, the level of Ki67 during G0 and G1 in individual cells is highly heterogeneous and depends on how long an individual cell has spent in G0. Thus, Ki67 is a graded rather than a binary marker both for cell-cycle progression and time since entry into quiescence.
| S-EPMC6108547 | biostudies-literature
Project description:The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is, however, not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly up-regulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Finally, we found that a gene-expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.
| S-EPMC6842626 | biostudies-literature
Project description:BackgroundAdjuvant chemotherapy has been shown to produce a favorable prognosis for patients with resectable mucosal melanoma (MM), resulting in the need for stratification to optimally select patients to benefit from adjuvant therapy. This study analyzed Ki67 as a potential stratification index for adjuvant chemotherapy in resectable MM.MethodsPatients with resected MM who received subsequent adjuvant therapy in Beijing Cancer Hospital between 2010 and 2018 were retrospectively enrolled and analyzed. Relapse-free survival (RFS) and melanoma-specific survival (MSS) curves were used to perform the survival comparisons across different subgroups.ResultsFrom Jan 2010 to Dec 2018, 1106 MM patients were screened from a database of 4706 patients and 175 of these patients were finally enrolled. A total of 100 patients received temozolomide (TMZ)-based adjuvant chemotherapy and 75 patients received high-dose interferon-α2b (HDI) adjuvant therapy. Compared with HDI, patients who received TMZ-based adjuvant chemotherapy had significantly superior RFS (21.0 vs. 9.6 months, P = 0.002). For patients with low Ki67 expression (<30%), the two regimens showed no significant difference for impact on RFS (33.9 vs. 22.7 months, P = 0.329). However, for patients with high Ki67 expression (≥30%), TMZ-based adjuvant chemotherapy achieved favorable RFS compared with HDI (18.0 vs. 6.7 months, P < 0.001) and tended to improve MSS compared to HDI (41.4 vs. 25.1 months, P = 0.067).ConclusionCompared with HDI, adjuvant chemotherapy may be more relevant for patients with Ki67 ≥ 30%. Ki67 may serve as a potential index to distinguish populations benefiting from adjuvant chemotherapy in resectable MM, and may provide a basis for stratification in the selection of adjuvant regimens.
| S-EPMC9280123 | biostudies-literature
Project description:The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is however not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly upregulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Lastly, we found that a gene expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.
2019-10-11 | GSE124109 | GEO
Project description:Established measurements of proliferation in breast cancer are Ki67 and mitotic-activity-index (MAI), with problems in reproducibility and prognostic accuracy. Phosphohistone H3 (PHH3), a relatively novel IHC marker is specific for mitosis with good reproducibility. We hypothesized that PHH3 would be more reproducible and better represent proliferation than Ki67.PHH3 identified easily-missed mitosis by MAI, as demonstrated by upgrading M grade at diagnosis (n = 29/218, evenly distributed). PHH3 accurately found hot-spots, supported by mitotic count agreement between low-power and 10HPFs (R2 = 0.999; P = 0.001). PHH3 was more reproducible than Ki67, measured by five-rater inter-class correlation coefficient (0.904 > 0.712; P = 0.008). Finally, despite a relatively short follow-up (median 46 months; 7 recurrences) PHH3 was the only variable correlated with disease-free survival (P = 0.043), while all other conventional clinicopathologic variables, including Ki67 (P = 0.356), did not.We compared Ki67 and PHH3 for 218 breast cancer surgical cases diagnosed from 2012 to 2013 at Severance hospital. The most representative invasive breast cancer surgical slides were immunohistochemically stained for Ki67 and PHH3.Poor reproducibility and inadequate representation of proliferation of Ki67 and MAI may be improved by PHH3, allowing better accuracy in breast cancer diagnostics.
| S-EPMC5630312 | biostudies-literature
Project description:Uncontrolled proliferation is a hallmark of cancer and can be assessed by labelling breast tissue using immunohistochemistry for Ki67, a protein associated with cell proliferation. Accurate measurement of Ki67-positive tumour nuclei is of critical importance, but requires annotation of the tumour regions by a pathologist. This manual annotation process is highly subjective, time-consuming and subject to inter- and intra-annotator experience. To address this challenge, we have developed Proliferation Tumour Marker Network (PTM-NET), a deep learning model that objectively annotates the tumour regions in Ki67-labelled breast cancer digital pathology images using a convolution neural network. Our custom designed deep learning model was trained on 45 immunohistochemical Ki67-labelled whole slide images to classify tumour and non-tumour regions and was validated on 45 whole slide images from two different sources that were stained using different protocols. Our results show a Dice coefficient of 0.74, positive predictive value of 70% and negative predictive value of 88.3% against the manual ground truth annotation for the combined dataset. There were minimal differences between the images from different sources and the model was further tested in oestrogen receptor and progesterone receptor-labelled images. Finally, using an extension of the model, we could identify possible hotspot regions of high proliferation within the tumour. In the future, this approach could be useful in identifying tumour regions in biopsy samples and tissue microarray images.
| S-EPMC6731323 | biostudies-literature
Project description:Nervous systems are incredibly diverse, with myriad neuronal subtypes defined by gene expression. How binary and graded fate characteristics are patterned across tissues is poorly understood. Expression of opsin photopigments in the cone photoreceptors of the mouse retina provides an excellent model to address this question. Individual cones express S-opsin only, M-opsin only, or both S-opsin and M-opsin. These cell populations are patterned along the dorsal-ventral axis, with greater M-opsin expression in the dorsal region and greater S-opsin expression in the ventral region. Thyroid hormone signaling plays a critical role in activating M-opsin and repressing S-opsin. Here, we developed an image analysis approach to identify individual cone cells and evaluate their opsin expression from immunofluorescence imaging tiles spanning roughly 6 mm along the D-V axis of the mouse retina. From analyzing the opsin expression of ~250,000 cells, we found that cones make a binary decision between S-opsin only and co-expression competent fates. Co-expression competent cells express graded levels of S- and M-opsins, depending nonlinearly on their position in the dorsal-ventral axis. M- and S-opsin expression display differential, inverse patterns. Using these single-cell data, we developed a quantitative, probabilistic model of cone cell decisions in the retinal tissue based on thyroid hormone signaling activity. The model recovers the probability distribution for cone fate patterning in the mouse retina and describes a minimal set of interactions that are necessary to reproduce the observed cell fates. Our study provides a paradigm describing how differential responses to regulatory inputs generate complex patterns of binary and graded cell fates.
| S-EPMC7082072 | biostudies-literature
Project description:The proliferation-quiescence decision is a dynamic process that remains incompletely understood. Live-cell imaging with fluorescent cell cycle sensors now allows us to visualize the dynamics of cell cycle transitions and has revealed that proliferation-quiescence decisions can be highly heterogeneous, even among clonal cell lines in culture. Under normal culture conditions, cells often spontaneously enter non-cycling G0 states of varying duration and depth. This also occurs in cancer cells and G0 entry in tumors may underlie tumor dormancy and issues with cancer recurrence. Here we show that a cell cycle indicator previously shown to indicate G0 upon serum starvation, mVenus-p27K-, can also be used to monitor spontaneous quiescence in untransformed and cancer cell lines. We find that the duration of spontaneous quiescence in untransformed and cancer cells is heterogeneous and that a portion of this heterogeneity results from asynchronous proliferation-quiescence decisions in pairs of daughters after mitosis, where one daughter cell enters or remains in temporary quiescence while the other does not. We find that cancer dormancy signals influence both entry into quiescence and asynchronous proliferation-quiescence decisions after mitosis. Finally, we show that spontaneously quiescent prostate cancer cells exhibit altered expression of components of the Hippo pathway and are enriched for the stem cell markers CD133 and CD44. This suggests a hypothesis that dormancy signals could promote cancer recurrence by increasing the proportion of quiescent tumor cells poised for cell cycle re-entry with stem cell characteristics in cancer.
| S-EPMC8703172 | biostudies-literature
Project description:Due to contradictious findings of previous studies regarding Ki67's value in gastric cancer (GC), we reevaluated the expression of Ki67 in whole tissue sections (WTS) and tissue microarrays (TMAs) of GC testing the following hypotheses: does Ki67 show intratumoral heterogeneity; are TMAs representative in the determination of the Ki67 proliferation index (PI); is the Ki67 PI subject to an intralaboratory variability; and is the Ki67 PI related to clinico-pathological patient characteristics and/or prognostically relevant in GC.Corresponding WTS and TMAs samples from 315 GCs were stained immunohistochemically. The Ki67 PI evaluated on WTS was correlated with the Ki67 PI evaluated on TMAs, sample age, clinico-pathological characteristics, and patient survival.The overall amount of Ki67-positive tumor cells did not depend on sample age. Three distinct, partly heterogeneous Ki67 expression patterns were observed. The mean Ki67 PI evaluated on TMAs differed on average minus 16.9% from the Ki67 PI evaluated on WTS. Ki67 in WTS correlated significantly with the Laurén phenotype and tumor grade, but not with patient survival.TMAs carry the risk of a systematic underestimation of the Ki67 PI. Ki67 has no prognostic value in GC but might be a potential indicator of intratumoral heterogeneity.
| S-EPMC4736456 | biostudies-literature
Project description:Our objective was to examine the usefulness of the Ki67 proliferation index as a prognostic marker in patients with medullary thyroid carcinoma (MTC). It is difficult to predict the prognosis of MTC by using conventional prognostic factors. Immunocytochemical analysis of tumour proliferation has been used as a prognostic tool in some tumours, but only rarely in MTC. In all, 71 tumours from 36 patients were investigated, by using a semiautomatic image analysis programme. On average 10,000 nuclear profiles were counted per tumour, and the percentage of tumour cells expressing the proliferation marker, Ki67, was calculated. Primary tumours that had metastasised had higher Ki67 indices than primary tumours that had not metastasised. Recurrent lymph node metastasis had higher Ki67 indices than the primary tumours. By using a Poisson model, it was possible to estimate the median survival time for individual patients if the Ki67 index for the primary tumour and the age at surgery were known. The higher the Ki67 index and the age at operation were, the shorter was the survival. Estimating the median survival of individual patients will be of help for planning the patients' life and postoperative follow-up and treatment.
| S-EPMC2376863 | biostudies-other