Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.3022

The cell cycle and cancer.

Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biologic level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biologic insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately downregulate the RAS/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance.

https://cancerres.aacrjournals.org/content/canres/75/23/5014.full.pdf

Mechanisms of Cancer Cell Dormancy—Another Hallmark of Cancer?

Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating “G0-like” progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small-molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.

https://www.pnas.org/content/pnas/108/31/12845.full.pdf

Asymmetric cancer cell division regulated by AKT

The σ2 receptor is an important target for the development of molecular probes in oncology because of its 10-fold higher density in proliferating tumor cells compared with that in quiescent tumor cells and because of the observation that σ2 receptor agonists are able to kill tumor cells via apoptotic and nonapoptotic mechanisms. Although recent evidence indicates that the σ2 receptor binding site is localized within the progesterone receptor membrane component 1 (PGRMC1), most information regarding this protein has been obtained using either radiolabeled or fluorescent receptor-based probes and from biochemical analysis of the effect of σ2 selective ligands on cells grown in culture. This article reviews the development of σ2 receptor ligands and presents an overview of how they have been used in vitro and in vivo to increase our understanding of the role of the σ2 receptor in cancer and proliferation.

The σ2 Receptor: A Novel Protein for the Imaging and Treatment of Cancer

Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify the molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells, in which a selected gene was stably knocked down were injected into the tail veins of mice, and the formation of tumors in the lungs was monitored. One of the several genes found to be important for tumor growth in the lungs was NIMA-related kinases 2 (Nek2), a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad. In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 has a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells

Multiparameter analysis of core regulatory proteins involved in G1–S and G2–M cell-cycle transitions provides a powerful biomarker readout for assessment of the cell-cycle state. We have applied this algorithm to breast cancer to investigate how the cell cycle impacts on disease progression. Protein expression profiles of key constituents of the DNA replication licensing pathway (Mcm2, geminin) and mitotic machinery (Plk1, Aurora A and the Aurora substrate histone H3S10ph) were generated for a cohort of 182 patients and linked to clinicopathological parameters. Arrested differentiation and genomic instability were associated with an increased engagement of cells into the cell division cycle (P<0.0001). Three unique cell-cycle phenotypes were identified: (1) well-differentiated tumours composed predominantly of Mcm2-negative cells, indicative of an out-of-cycle state (18% of cases); (2) high Mcm2-expressing tumours but with low geminin, Aurora A, Plk1 and H3S10ph levels (S–G2–M progression markers), indicative of a G1-delayed/arrested state (24% cases); and (3) high Mcm2-expressing tumours and also expressing high levels of the S–G2–M progression markers, indicative of accelerated cell-cycle progression (58% of cases). The active cell-cycle progression phenotype had a higher risk of relapse when compared with out-of-cycle and G1-delayed/arrested phenotypes (HR=3.90 (1.81–8.40, P<0.001)), and was associated with Her-2 and triple negative subtypes (P<0.001). It is of note that high-grade tumours with the G1-delayed/arrested phenotype showed an identical low risk of relapse compared with well-differentiated out-of-cycle tumours (HR=1.00 (0.22–4.46), P=0.99). Our biomarker algorithm provides novel insights into the cell-cycle state of dynamic tumour cell populations in vivo. This information is of major prognostic significance and may impact on individualised therapeutic decisions. Patients with an accelerated phenotype are more likely to derive benefit from S- and M-phase-directed chemotherapeutic agents.

/pdf/cell-cycle-phase-progression-analysis-identifies-unique-245zolj9zw.pdf

Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts

Abstract #5066 

BACKGROUND: The cell cycle machinery acts as an integration point for information transduced through complex and redundant upstream oncogenic signalling pathways Multiparameter analysis of core regulatory proteins involved in G1-S and G2-M cell cycle phase transitions provides a powerful biomarker readout for assessment of the cell cycle state We have applied this novel algorithm to breast cancer, investigating its cell cycle kinetics, and determining how this impacts on pathobiology and disease progression in-vivo METHODS AND FINDINGS: Protein expression profiles of key constituents of the DNA replication licensing pathway (Mcm2, geminin) and mitotic machinery (Plk1, Aurora A, Aurora substrate Histone H3S10ph), mediators of G1-S and G2-M transition respectively, were generated for a cohort of 182 patients Arrested differentiation and development of genomic instability was associated with increased engagement of cells into the cell division cycle (p<00001) Three unique cell cycle phenotypes were identified; (I) well differentiated tumours composed predominantly of Mcm2 negative cells indicative of an out-of-cycle state (18% of cases), (II) high Mcm2 expressing tumours but with low geminin, Aurora A, Plk1 and H3S10ph levels (S-G2-M progression markers) indicative of a G1 delayed/arrested state (24% cases), (III) high expressing Mcm2 tumours, but also expressing high levels of the S-G2-M progression markers, indicative of accelerated cell cycle progression (58% of cases) The accelerated cell cycle phenotype had a significantly higher risk of relapse when compared with out-of-cycle and G1 delayed/arrested tumour phenotypes (HR=390 [181-840], p<0001) Notably high grade tumours with the G1 delayed/arrested phenotype showed an identical low risk of relapse to well differentiated out-of-cycle tumours (HR=100 [022-446], p=099), suggesting that many patients are receiving inappropriate S-G2-M phase directed adjuvant chemotherapy CONCLUSIONS: This biomarker algorithm provides novel insights into the cell cycle state of dynamic tumour cell populations in-vivo, information that impacts on individualised therapeutic decisions The cell cycle phenotype has a major influence on disease progression, identifying those patients at most risk of relapse Importantly, it is only patients displaying an accelerated phenotype, tumours that show S-G2-M phase transit, that are likely to derive benefit from S and G2-M phase specific adjuvant chemotherapeutic agents and mechanistic drugs

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5066

J Young

Papers

Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer

Cell cycle phase progression analysis identifies unique replication phenotypes of major prognostic and predictive significance in cancer.