Nuclear morphometry, nucleomics and prostate cancer progression

Abstract

Prostate cancer (PCa) results from a multistep process. This process includes initiation, which occurs through various aging events and multiple insults (such as chronic infection, inflammation and genetic instability through reactive oxygen species causing DNA double-strand breaks), followed by a multistep process of progression. These steps include several genetic and epigenetic alterations, as well as alterations to the chromatin structure, which occur in response to the carcinogenic stress-related events that sustain proliferative signaling. Events such as evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis are readily observed. In addition, in conjunction with these critical drivers of carcinogenesis, other factors related to the etiopathogenesis of PCa, involving energy metabolism and evasion of the immune surveillance system, appear to be involved. In addition, when cancer spread and metastasis occur, the 'tumor microenvironment' in the bone of PCa patients may provide a way to sustain dormancy or senescence and eventually establish a 'seed and soil' site where PCa proliferation and growth may occur over time. When PCa is initiated and progression ensues, significant alterations in nuclear size, shape and heterochromatin (DNA transcription) organization are found, and key nuclear transcriptional and structural proteins, as well as multiple nuclear bodies can lead to precancerous and malignant changes. These series of cellular and tissue-related malignancy-associated events can be quantified to assess disease progression and management.

Sizing and shaping the nucleus: mechanisms and significance

“…Lamin A was identified as a potential new biomarker for prostate cancer progression, which is associated with altered nuclear size, shape, and heterochromatin organization. Compared to benign samples, lamin A was downregulated in low grade tumors and upregulated in high grade tumors [99,100]. Tumor regression in response to treatment of breast cancer with anti-estrogen therapy was associated with decreased nuclear size in tumor cells, suggesting that reductions in nuclear size might be used to assess treatment efficacy [101].…”

Epithelial-mesenchymal transition in prostate cancer is associated with quantifiable changes in nuclear structure

“…The cell nucleus in cancer is subject to genetic instability from DNA double-strand breaks leading to significant alterations in nuclear size, shape, and chromatin texture that may promote proliferative signaling, cancer progression, and malignancy [9]. Quantitative analysis of cancer cell nuclear morphology has been used to distinguish cancer aggressiveness, Gleason grade, and heterogeneity on the basis of this cancer-associated nuclear remodeling [10][11][12][13][14][15][16].…”

Development of a Nuclear Morphometric Signature for Prostate Cancer Risk in Negative Biopsies

“…However, despite numerous reports of success using a variety of approaches and striking improvements in both hardware and software, computer-assisted nuclear morphometry still has abundant undeveloped potential for the discovery of useful biomarkers in PCa research [2], [3]. Veltri, et al recently published an excellent review encompassing the history and evolution of this field [4].…”