A pinboard by
Vibishan B

PhD student, Indian Institute of Science Education and Research (IISER), Pune


Implications of context-dependent somatic cell competition for carcinogenesis and cancer incidence

As Robert Weinberg points out in his book, One Renegade Cell, cancer was recognized as a micro-evolutionary process very early on. However, progress on developing this into a more rigorous approach came much later with Peter Nowell's landmark paper on the clonal evolution of tumour populations. I seek to pursue this application to further address several outstanding issues regarding cancer. The current view of carcinogenesis is that of cell competition; mutant cells compete with their non-mutant neighbours for resources, including space and nutrition. This competition selects for mutations that allow for uncontrolled, growth factor-independent cell growth, eventually culminating in a cancerous cellular phenotype. By explicitly accounting for selective processes, this allows us to address the role of differences in the cellular environment in the outcome of somatic competition.

This is represents a gap in the current understanding of carcinogenesis; while it has been recognized that multi-stage accumulation of mutations is key to cancer progression, the fact that cell competition is context-dependent is yet to gain much traction in the field. The argument is a simple one-individuals vary in their tissue architecture and micro-environmental conditions, and these differences impose selection pressures specific to these conditions. Such differences could arise out of different lifestyles, behavioural regimes, or direct environmental factors, and they play a key role in determining whether a given mutation leads to cancer or not. Evidence for such context dependence is emerging already, some of which is attached here. We, my PI and I, have tested these three models of cancer-random chance, simple cell competition and context dependence-with a simulation model, and have found that context dependence is a necessary condition to replicate epidemiological trends of cancer incidence with age. It is also worth noting that our analyses reveal the need to re-evaluate the canonical assumption that cancer incidence has a power law relationship with age. On that premise, we have responded to Tomasetti et al.'s recent publication, pointing out similar assumptions. We hope to continue with this mode of hypothesis testing and elimination based on epidemiological data from sources like the SEER program, and more rigorous statistical analysis. We also plan to carry out cell competition in vitro to demonstrate that advantages of oncogenic mutations are context-dependent.


Effect of acute exercise on prostate cancer cell growth.

Abstract: Physical activity is associated with reduced risk of several cancers, including aggressive prostate cancer. The mechanisms mediating the effects are not yet understood; among the candidates are modifications of endogenous hormone levels. Long-term exercise is known to reduce serum levels of growth stimulating hormones. In contrast, the endocrine effects of acute endurance exercise include increased levels of mitogenic factors such as GH and IGF-1. It can be speculated that the elevation of serum growth factors may be detrimental to prostate cancer progression into malignancy. The incentive of the current study is to evaluate the effect of acute exercise serum on prostate cancer cell growth. We designed an exercise intervention where 10 male individuals performed 60 minutes of bicycle exercise at increasing intensity. Serum samples were obtained before (rest serum) and after completed exercise (exercise serum). The established prostate cancer cell line LNCaP was exposed to exercise or rest serum. Exercise serum from 9 out of 10 individuals had a growth inhibitory effect on LNCaP cells. Incubation with pooled exercise serum resulted in a 31% inhibition of LNCaP growth and pre-incubation before subcutaneous injection into SCID mice caused a delay in tumor formation. Serum analyses indicated two possible candidates for the effect; increased levels of IGFBP-1 and reduced levels of EGF. In conclusion, despite the fear of possible detrimental effects of acute exercise serum on tumor cell growth, we show that even the short-term effects seem to add to the overall beneficial influence of exercise on neoplasia.

Pub.: 19 Jul '13, Pinned: 17 Jun '17

Dynamic and influential interaction of cancer cells with normal epithelial cells in 3D culture.

Abstract: The cancer microenvironment has a strong impact on the growth and dynamics of cancer cells. Conventional 2D culture systems, however, do not reflect in vivo conditions, impeding detailed studies of cancer cell dynamics. This work aims to establish a method to reveal the interaction of cancer and normal epithelial cells using 3D time-lapse.GFP-labelled breast cancer cells, MDA-MB-231, were co-cultured with mCherry-labelled non-cancerous epithelial cells, MDCK, in a gel matrix. In the 3D culture, the epithelial cells establish a spherical morphology (epithelial sphere) thus providing cancer cells with accessibility to the basal surface of epithelia, similar to the in vivo condition. Cell movement was monitored using time-lapse analyses. Ultrastructural, immunocytochemical and protein expression analyses were also performed following the time-lapse study.In contrast to the 2D culture system, whereby most MDA-MB-231 cells exhibit spindle-shaped morphology as single cells, in the 3D culture the MDA-MB-231 cells were found to be single cells or else formed aggregates, both of which were motile. The single MDA-MB-231 cells exhibited both round and spindle shapes, with dynamic changes from one shape to the other, visible within a matter of hours. When co-cultured with epithelial cells, the MDA-MB-231 cells displayed a strong attraction to the epithelial spheres, and proceeded to surround and engulf the epithelial cell mass. The surrounded epithelial cells were eventually destroyed, becoming debris, and were taken into the MDA-MB-231 cells. However, when there was a relatively large population of normal epithelial cells, the MDA-MB-231 cells did not engulf the epithelial spheres effectively, despite repeated contacts. MDA-MB-231 cells co-cultured with a large number of normal epithelial cells showed reduced expression of monocarboxylate transporter-1, suggesting a change in the cell metabolism. A decreased level of gelatin-digesting ability as well as reduced production of matrix metaroproteinase-2 was also observed.This culture method is a powerful technique to investigate cancer cell dynamics and cellular changes in response to the microenvironment. The method can be useful for various aspects such as; different combinations of cancer and non-cancer cell types, addressing the organ-specific affinity of cancer cells to host cells, and monitoring the cellular response to anti-cancer drugs.

Pub.: 08 Nov '14, Pinned: 07 Jun '17

Evolutionary foundations for cancer biology.

Abstract: New applications of evolutionary biology are transforming our understanding of cancer. The articles in this special issue provide many specific examples, such as microorganisms inducing cancers, the significance of within-tumor heterogeneity, and the possibility that lower dose chemotherapy may sometimes promote longer survival. Underlying these specific advances is a large-scale transformation, as cancer research incorporates evolutionary methods into its toolkit, and asks new evolutionary questions about why we are vulnerable to cancer. Evolution explains why cancer exists at all, how neoplasms grow, why cancer is remarkably rare, and why it occurs despite powerful cancer suppression mechanisms. Cancer exists because of somatic selection; mutations in somatic cells result in some dividing faster than others, in some cases generating neoplasms. Neoplasms grow, or do not, in complex cellular ecosystems. Cancer is relatively rare because of natural selection; our genomes were derived disproportionally from individuals with effective mechanisms for suppressing cancer. Cancer occurs nonetheless for the same six evolutionary reasons that explain why we remain vulnerable to other diseases. These four principles-cancers evolve by somatic selection, neoplasms grow in complex ecosystems, natural selection has shaped powerful cancer defenses, and the limitations of those defenses have evolutionary explanations-provide a foundation for understanding, preventing, and treating cancer.

Pub.: 12 Feb '13, Pinned: 07 Jun '17