Increase, Cell Proliferation leads to Increase, lung cancer

Uncertainties in this KER are as follows:

1. Inconsistencies in results were observed in studies using radiation as a stressor.The dose threshold for the onset of proliferation and lung cancer induction varies with radiation quality, individual cell sensitivity, and confounding factors (Taylor 2013).  The latter two are also be true for chemical carcinogens (Malhotra et al., 2016).

Not identified.

Studies that directly assessed the time scale between increased cellular proliferation and lung carcinogenesis are lacking. There are some studies, however, that provide details regarding the timing between these two events. In vitro experiments using lung cancer cell lines demonstrated that expression levels of key proteins involved in the regulation of the cell cycle and/or proliferation were modified by chemical inhibitors within the first 48 hours of treatment. Delphinidin caused changes in the expression levels of EGFR, pEGFR, VEGFR2 and pVEGFR2 within the first 3 hours (Pal et al. 2013), and pargyline decreased LSD1 levels within 6 hours of treatment (Lv et al. 2012). Delphinidin-induced changes to the expression of PI3K/p110, PI3K/p85, pAKT, pERK1/2, pJNK1/2, pp38, PCNA and cyclin-D1 were documented within 48 hours of treatment (Pal et al. 2013). Similarly, CAT application led to significant declines in cell cycle checkpoint proteins cyclin-D1, CDK4 and CDK6 by 36 hours post-treatment (Wanitchakool et al. 2012). Additionally, changes to the cell cycle were evident within 24 - 48 hours of CAT treatment (Wanitchakool et al. 2012), and within 48 hours of ZIC5 knockdown with silencing RNA (Sun et al. 2016). ZIC5 knockdown also caused declines in cell proliferation by 96 hours post-transfection, and declines in clone formation after 2 weeks (Sun et al. 2016). Overall, these in vitro studies demonstrate that modifications to both cell cycle regulation and cell proliferation rates in cancer cells can be affected within hours to days of a perturbance. 

In vivo studies also provide information regarding the timescale between cell proliferation and tumourigenesis. Tumours in xenograft nude mice were detected within two weeks of NSCLC-cell inoculation (Pal et al. 2013; Warin et al. 2014; Sun et al. 2016; Tu et al. 2018), with one study showing tumour detection as early as 1 week post-inoculation (Warin et al. 2014).Tumours continued to grow over the experimental period until time of harvest (Pal et al. 2013; Warin et al. 2014; Sun et al. 2016; Tu et al. 2018). Differences in tumour growth rates between treated and untreated mice were evident within 13 -16 days of delphinidin treatment (Pal et al. 2013), 3 weeks of ZIC5 knock-down (Sun et al. 2016), and by 27 days of either taurine, PUMA or taurine and PUMA treatment (Tu et al. 2018). At the time of xenograft nude mouse tumour harvest (which varied between 22 days and 27 weeks), there were significant differences in markers of cell proliferation and tumour size or number in mice exposed to anti-cancer compounds and their respective controls (Kassie et al. 2008; Pal et al. 2013; Warin et al. 2014; Sun et al. 2016; Tu et al. 2018). In non-xenograft mice exposed to a high levels of tobacco smoke, increased markers of cell proliferation and the incidence of airway squamous metaplasia was evident upon sacrifice after 14 weeks of constant tobacco smoke exposure (Zhong et al. 2005).

Usually, non-cancerous cells are stimulated by growth factors originating from other cell types. For cancer cell lines, cell proliferation rates can be increased by autocrine signalling. Some cancer cells acquire the ability to produce both the growth factors and the required receptors, thus allowing the cell to respond to its own growth signals, and further stimulate more cell proliferation (Hanahan and Weinberg 2011).