The hallmarks of premalignant conditions: a molecular basis for cancer prevention

Ryan, Bríd M.; Faupel-Badger, Jessica M.

doi:10.1053/j.seminoncol.2015.09.007

Cited by 31 publications

(19 citation statements)

References 180 publications

(204 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cervical cancer is a spectrum of disease with a gradual progression from premalignant condition to aggressive disease. 1 The onset of the disease begins in the cervix, which later spreads towards the lower uterine segment, vagina, para-cervical space, along with the broad and uterosacral ligaments. Current treatment approaches involve mainly the use of intensive chemotherapy, aided by radiotherapy and surgery.…”

Section: Introductionmentioning

confidence: 99%

<p>Effects of Nicotinamide on Cervical Cancer-Derived Fibroblasts: Evidence for Therapeutic Potential</p>

Hassan¹,

Luo²

2020

CMAR

View full text Add to dashboard Cite

The present study aimed to examine the effects of nicotinamide (NAM) on cervical cancer-associated fibroblasts (CAF) for its in vitro efficacy, gross inhibition, and mechanism of inhibition. Methods: The fibroblasts were treated with pre-specified concentrations of NAM followed by measurement of the cell proliferation using CCK-8 assay. The production of reactive oxygen species (ROS) was measured by 2ʹ,7ʹ-Dichlorofluorescin diacetate. We further investigated the apoptosis by flow cytometry using Annexin-V. We employed JC-1 assay to detect changes in the potential of the mitochondrial membrane. We further determined the expression of apoptotic genes was measured using qRT-PCR. And lastly, cell cycle experiments were conducted to determine the influence of NAM on arresting the growth of CAF in a cell cycle. Results: Our study showed that NAM was able to reduce fibroblasts viability. We specifically observed a significantly increased intracellular ROS with resultant exhaustion of cellular antioxidant defense machinery, including reduced glutathione (GSH). We further observed the involvement of mitochondrial pathway in the NAM induced apoptosis of fibroblasts. Conclusion: Our study supports the therapeutic potential of NAM for the treatment of cervical cancer and necessitates a further investigation of the reported findings.

show abstract

Section: Introductionmentioning

confidence: 99%

<p>Effects of Nicotinamide on Cervical Cancer-Derived Fibroblasts: Evidence for Therapeutic Potential</p>

Hassan¹,

Luo²

2020

CMAR

View full text Add to dashboard Cite

show abstract

“…Most epithelial cancers are preceded by pre-malignant lesions which frequently display mutations in cancer driver genes (54–57). Nevertheless, early and late events are not universally characterized in most epithelial tumors, with the exception of colorectal cancer, where tumor progression has been thoroughly dissected in terms of stepwise accumulation of somatic mutations.…”

Section: Discussionmentioning

confidence: 99%

In silicolearning of tumor evolution through mutational time series

Auslander

Wolf

Koonin

2019

Preprint

View full text Add to dashboard Cite

10Cancer arises through the accumulation of somatic mutations over time. Understanding the 11 sequence of mutation occurrence during cancer progression can assist early and accurate 12 diagnosis and improve clinical decision-making. Here we employ Long Short-Term Memory 13 networks (LSTMs), a class of recurrent neural network, to learn the evolution of a tumor through an 14 ordered sequence of mutations. We demonstrate the capacity of LSTMs to learn complex dynamics 15 of the mutational time series governing tumor progression, allowing accurate prediction of the 16 mutational burden and the occurrence of mutations in the sequence. Using the probabilities learned 17 by the LSTM, we simulate mutational data and show that the simulation results are statistically 18 indistinguishable from the empirical data. We identify passenger mutations that are significantly 19 associated with established cancer drivers in the sequence and demonstrate that the genes carrying 20 these mutations are substantially enriched in interactions with the corresponding driver genes. 21Breaking the network into modules consisting of driver genes and their interactors, we show that 22 these interactions are associated with poor patient prognosis, thus likely conferring growth 23 advantage for tumor progression. Thus, application of LSTM provides for prediction of 24 numerous additional conditional drivers and to reveal hitherto unknown aspects of cancer 25 evolution. 26 27 Significance 28 29Cancer is caused by the effects of somatic mutations known as drivers. Although a number of 30 major cancer drivers have been identified, it is suspected that many more comparatively rare and 31 conditional drivers exist, and the interactions between different cancer-associated mutations that 32 might be relevant for tumor progression are not well understood. We applied an advanced neural 33 network approach to learn the sequence of mutations and the mutational burden in colon and 34 lung cancers, and to identify mutations that are associated with individual drivers. A significant 35ordering of driver mutations is demonstrated, and numerous, previously undetected conditional 36 drivers are identified. These findings broaden the existing understanding of the mechanisms of 37 tumor progression and have implications for therapeutic strategies. 38 learning algorithms could be applied to the sequence of somatic mutations, potentially revealing 62 the complex dynamics of the tumor evolution and enabling a variety of context-specific 63 predictions. 64 65To this end, we employed Long Short Term Memory (LSTM) networks (20), a type of Recurrent 66Neural Networks (21) capable of learning long-term dependencies in a time series sequence. These 67 networks have achieved major success in time-series prediction tasks and for learning evolution of 68 recurrent systems (20,(22)(23)(24). We demonstrate here the utility of applying LSTM to time-ordered 69 mutational data in colon and lung adenocarcinomas. We define a pseudo-temporal gene ranking, 70representing each tumor s...

show abstract

“…The hallmarks of cancer in premalignant cell phenotypes are characterized by the dependence on signaling growth and later on self‐sufficiency in growth signals. This is consistent with our evidence of premalignant features of non‐tumorigenic cells after exposure to the Nic‐NNK combination . On the other hand, malignant cell phenotypes, such as invasion ability or enrichment with the CSCs markers, were also detected significantly at the earlier for cells induced by Nic‐NNK combination, compared with untreated cells.…”

Section: Discussionmentioning

confidence: 99%

Long‐term exposure to extremely low‐dose of nicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) induce non‐malignant breast epithelial cell transformation through activation of the a9‐nicotinic acetylcholine receptor‐mediated signaling pathway

Fararjeh

Chen

et al. 2018

Environmental Toxicology

View full text Add to dashboard Cite

Breast cancer (BC) is the most common cancer affecting women worldwide and has been associated with active tobacco smoking. Low levels of nicotine (Nic) and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK), have been detected in cases of second‐hand smoke (SHS). However, the correlation between SHS and BC risk remains controversial. In this study, we investigated whether the physiological SHS achievable dose of Nic and tobacco specific nitrosamine, NNK act together to induce breast carcinogenesis using an in vitro breast cell carcinogenesis model. Immortalized non‐tumorigenic breast epithelial cell line, HBL‐100 used for a time‐course assay, was exposed to very low levels of either Nic or NNK, or both. The time‐course assay consisted of 23 cycles of nitrosamines treatment. In each cycle, HBL‐100 cells were exposed to 1pM of Nic and/or 100 femtM of NNK for 48 hours. Cells were passaged every 3 days and harvested after 10, 15, and 23 cycles. Our results demonstrated that the tumorigenicity of HBL‐100, defined by soft agar colony forming, proliferation, migration and invasion abilities, was enhanced by co‐exposure to physiologically SHS achievable doses of Nic and NNK. In addition, α9‐nAChR signaling activation, which plays an important role in cellular proliferation and cell survival, was also observed. Importantly, an increase in stemness properties including the prevalence of CD44+/CD24− cells, increase Nanog expression and mammosphere‐forming ability were also observed. Our results indicate that chronic and long term exposure to environmental tobacco smoke, may induce breast cell carcinogenesis even at extremely low doses.

show abstract

The hallmarks of premalignant conditions: a molecular basis for cancer prevention

Cited by 31 publications

References 180 publications

<p>Effects of Nicotinamide on Cervical Cancer-Derived Fibroblasts: Evidence for Therapeutic Potential</p>

<p>Effects of Nicotinamide on Cervical Cancer-Derived Fibroblasts: Evidence for Therapeutic Potential</p>

In silicolearning of tumor evolution through mutational time series

Long‐term exposure to extremely low‐dose of nicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) induce non‐malignant breast epithelial cell transformation through activation of the a9‐nicotinic acetylcholine receptor‐mediated signaling pathway

Contact Info

Product

Resources

About