Publisher Correction: 3D Shape Modeling for Cell Nuclear Morphological Analysis and Classification.

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3D Shape Modeling for Cell Nuclear Morphological Analysis and Classification.

Quantitative analysis of morphological changes in a cell nucleus is important for the understanding of nuclear architecture and its relationship with pathological conditions such as cancer. However, dimensionality of imaging data, together with a great variability of nuclear shapes, presents challenges for 3D morphological analysis. Thus, there is a compelling need for robust 3D nuclear morphometric techniques to carry out population-wide analysis. We propose a new approach that combines modeling, analysis, and interpretation of morphometric characteristics of cell nuclei and nucleoli in 3D. We used robust surface reconstruction that allows accurate approximation of 3D object boundary. Then, we computed geometric morphological measures characterizing the form of cell nuclei and nucleoli. Using these features, we compared over 450 nuclei with about 1,000 nucleoli of epithelial and mesenchymal prostate cancer cells, as well as 1,000 nuclei with over 2,000 nucleoli from serum-starved and proliferating fibroblast cells. Classification of sets of 9 and 15 cells achieved accuracy of 95.4% and 98%, respectively, for prostate cancer cells, and 95% and 98% for fibroblast cells. To our knowledge, this is the first attempt to combine these methods for 3D nuclear shape modeling and morphometry into a highly parallel pipeline workflow for morphometric analysis of thousands of nuclei and nucleoli in 3D.

Symmetry and symmetry breaking in cancer: a foundational approach to the cancer problem.

Symmetry and symmetry breaking concepts from physics and biology are applied to the problem of cancer. Three categories of symmetry breaking in cancer are examined: combinatorial, geometric, and functional. Within these categories, symmetry breaking is examined for relevant cancer features, including epithelial-mesenchymal transition (EMT); tumor heterogeneity; tensegrity; fractal geometric and information structure; functional interaction networks; and network stabilizability and attack tolerance. The new cancer symmetry concepts are relevant to homeostasis loss in cancer and to its origin, spread, treatment and resistance. Symmetry and symmetry breaking could provide a new way of thinking and a pathway to a solution of the cancer problem.

Niche inheritance: a cooperative pathway to enhance cancer cell fitness through ecosystem engineering.

Cancer cells can be described as an invasive species that is able to establish itself in a new environment. The concept of niche construction can be utilized to describe the process by which cancer cells terraform their environment, thereby engineering an ecosystem that promotes the genetic fitness of the species. Ecological dispersion theory can then be utilized to describe and model the steps and barriers involved in a successful diaspora as the cancer cells leave the original host organ and migrate to new host organs to successfully establish a new metastatic community. These ecological concepts can be further utilized to define new diagnostic and therapeutic areas for lethal cancers.

The cancer diaspora: Metastasis beyond the seed and soil hypothesis.

Do cancer cells escape the confinement of their original habitat in the primary tumor or are they forced out by ecologic changes in their home niche? Describing metastasis in terms of a simple one-way migration of cells from the primary to the target organs is an insufficient concept to cover the nuances of cancer spread. A diaspora is the scattering of people away from an established homeland. To date, "diaspora" has been a uniquely human term used by social scientists; however, the application of the diaspora concept to metastasis may yield new biologic insights as well as therapeutic paradigms. The diaspora paradigm takes into account, and models, several variables including: the quality of the primary tumor microenvironment, the fitness of individual cancer cell migrants as well as migrant populations, the rate of bidirectional migration of cancer and host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites. Ecologic scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies. For example, ecologic traps - habitats that lead to the extinction of a species - can be developed to attract cancer cells to a place where they can be better exposed to treatments or to cells of the immune system for improved antigen presentation. Merging the social science concept of diaspora with ecologic and population sciences concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire new ideas for therapy.

Bacterial survival strategies suggest rethinking cancer cooperativity.

Despite decades of a much improved understanding of cancer biology, we are still baffled by questions regarding the deadliest traits of malignancy: metastatic colonization, dormancy and relapse, and the rapid evolution of multiple drug and immune resistance. New ideas are needed to resolve these critical issues. Relying on finding and demonstrating parallels between collective behavior capabilities of cancer cells and that of bacteria, we suggest communal behaviors of bacteria as a valuable model system for new perspectives and research directions. Understanding the ways in which bacteria thrive in competitive habitats and their cooperative strategies for surviving extreme stress can shed light on cooperativity in tumorigenesis and portray tumors as societies of smart communicating cells. This may translate into progress in fathoming cancer pathogenesis. We outline new experiments to test the cancer cooperativity hypothesis and reason that cancer may be outsmarted through its own 'social intelligence'.

Changing the energy habitat of the cancer cell in order to impact therapeutic resistance.

Somatic cellular evolution is becoming a popular biological explanation for the common rapid development of resistance to almost every form of cancer therapy and against almost every form of advanced human solid tumors. As a result of the historical power of evolution within nature, this common biological interpretation of the failure of cancer therapy is leading to a growing despair for many investigators and a stronger turn toward prevention through lifestyle changes. The absolute explosion of molecular scientific discoveries since 1983, in the reductionist identification of specific cancer therapeutic targets, has failed to deliver the impact in the clinic that many of us would have hoped would have resulted by this time. Personalized molecular medicine may help us reclassify appropriate therapeutic subgroups, but will it significantly impact the overall specific survival times for all of the cancers combined within the organ type for the entire population? How might we approach this therapeutic dilemma by utilizing new therapeutic insights designed on proven principles of evolution? In other words, can we fight the development of therapeutic resistance in cancer cells by turning established aspects of evolution against the survival of cancer cells within the individual patient? Here we review the concepts of changing the heat habitat and microenvironment of the cancer cell to alter the higher order organization and function of DNA. We have proposed that heat may be a major factor in determining the lasting therapeutic effect on many types of far advanced metastatic tumors.

Challenges in clinical prostate cancer: role of imaging.

OBJECTIVE: This article reviews a recent 2-day workshop on prostate cancer and imaging technology that was conducted by the Cancer Imaging Program of the National Cancer Institute. The workshop dealt with research trends and avenues for improving imaging and applications across the clinical spectrum of the disease. CONCLUSION: After a summary of prostate cancer incidence and mortality, four main clinical challenges in prostate cancer treatment and management-diagnostic accuracy; risk stratification, initial staging, active surveillance, and focal therapy; prostate-specific antigen relapse after radiation therapy or radical prostatectomy; and assessing response to therapy in advanced disease-were discussed by the 55-member panel. The overarching issue in prostate cancer is distinguishing lethal from nonlethal disease. New technologies and fresh uses for established procedures make imaging effective in both assessing and treating prostate cancer.

High mobility group protein HMGI(Y) enhances tumor cell growth, invasion, and matrix metalloproteinase-2 expression in prostate cancer cells.

BACKGROUND: The high mobility group protein HMGI(Y) has oncogenic properties and correlates with an aggressive phenotype in prostate cancer. The molecular mechanisms involved in transformation associated with HMGI(Y) overexpression remain unknown. METHODS: The HMG-I isoform was transfected and overexpressed in nonmetastatic Dunning prostate cancer cells (G cells) without detectable HMGI(Y). The assays of cell proliferation, tumor formation, in vitro invasion, and cDNA microarray were performed to assess the effect of HMGI(Y) overexpression in the transfected G cells. RESULTS: Overexpression of HMG-I in G cells significantly increases cell proliferation and tumor growth and also modestly enhances in vitro invasion compared to mock transfectant. cDNA microarray revealed that expression of the matrix metalloproteinase-2 (MMP-2) proform was increased eightfold in G cells overexpressing HMG-I. CONCLUSIONS: Overexpression of HMG-I in prostate cancer cells enhances cell growth, invasion, and expression of the proform of MMP-2, which may initiate early steps involved in the metastatic cascade.

Nuclear matrix localization of high mobility group protein I(Y) in a transgenic mouse model for prostate cancer.

Nuclear shape and the underlying nuclear structure, the nuclear matrix in cancer cells. Since the NM composition is considered to maintain nuclear shape and architecture, nuclear matrix proteins (NMPs) may be involved in transformation. Our laboratory has recently characterized a subset of NMPs that are associated with prostate cancer development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. One of the identified NMPs, E3E, has a similar molecular weight (22 kDa) with a protein known as HMGI(Y). HMGI(Y) belongs to a group of non-histone and chromatin-associated proteins, high-mobility-group (HMG) proteins, and it has been shown to associate with the NM. HMGI(Y) has been reported to be elevated in different types of cancer including prostate cancer. In this study, we examined the expression of HMGI(Y) protein in the NMP composition of the TRAMP model during the progression from normal to neoplasia. The expression of HMGI(Y) in the NMP extracts of three prostatic epithelial cell lines derived from a 32-week TRAMP mouse: TRAMP-C1, TRAMP-C2, and TRAMP-C3 was also examined. Using both one-dimensional and high-resolution two-dimensional immunoblot analyses, we found that: (i) HMGI(Y) is a nuclear matrix protein expressed as two protein bands with MW of 22-24 kDa and (ii) HMGI(Y) expression is correlated with neoplastic and malignant properties in late stage TRAMP prostate tumors. Overall, these findings support the evidence that HMGI(Y) can be utilized as a marker and prognostic tool for prostate cancer.

Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen.

We have identified two synthetic oligonucleotides (aptamers) that bind to prostate cancer cells,with low nanomolar affinity, via the extracellular portion of the prostate-specificmembrane antigen (PSMA). These two specific aptamers were selected from an initial 40mer library of approximately 6 x 10(14) random-sequence RNA molecules for their ability to bind to a recombinant protein representing the extracellular 706 amino acids of PSMA, termed xPSM. Six rounds of in vitro selection were performed, enriching for xPSM binding as monitored by aptamer inhibition of xPSM N-acetyl-alpha-linked acid dipeptidase (NAALADase) enzymatic activity. By round six, 95% of the aptamer pool consisted of just two sequences. These two aptamers, termed xPSM-A9 and xPSM-A10, were cloned and found to be unique, sharing no consensus sequences. The affinity of each aptamer for PSMA was quantitated by its ability to inhibit NAALADase activity. Aptamer xPSM-A9 inhibits PSMA noncompetitively with an average K(i) of 2.1 nM, whereas aptamer xPSM-A10 inhibits competitively with an average K(i) of 11.9 nM. Distinct modes of inhibition suggest that each aptamer identifies a unique extracellular epitope of xPSM. One aptamer was truncated from 23.4 kDa to 18.5 kDa and specifically binds LNCaP human prostate cancer cells expressing PSMA but not PSMA-devoid PC-3 human prostate cancer cells. These are the first reported RNA aptamers selected to bind a tumor-associated membrane antigen and the first application of RNA aptamers to a prostate specific cell marker. These aptamers may be used clinically as NAALADase inhibitors or be modified to carry imaging agents and therapeutic agents directed to prostate cancer cells.