Cytoplasmic physicochemical factors drive malignant transformation by adapting bioenergetic settings

Abstract

While significant insights have been gained by a study of cancer genetics, the roles of the cytoplasm in regulating chemical processes during the transformation to malignancy are often less appreciated. The cytoplasm functions as a two-phase system consisting of an elastic solid phase (the cytomatrix) and a viscous liquid phase (the cytosol). This finding has led to the development of a tumor progression model based on a two-phase system that connects genetic alterations with the physicochemical processes necessary for sustaining and facilitating malignant growth. Here, we show that the energy required for tumor growth is, in part, required for the cytomatrix activity, which accelerates chemical reactions. The ability to regulate cytomatrix motor proteins provides a mechanism to control whether a genetic mutation is able to induce the energy needed for cancer to develop and offers innovative strategies for cancer treatment.

Graphical abstract

Fig. 1

KEGG-based analysis of ribosome footprints of the HCT-15 cells. (A, B) Overrepresented pathways in the cytomatrix and underrepresented pathways in the cytosol. (C, D) Overrepresented pathways in the cytosol and underrepresented pathways in the cytomatrix. Overrepresentation analysis (ORA) significance was determined as the –Log 10 q-value. Significance was achieved at an FDR-adjusted p-value <0.05. CMX – cytomatrix, Cyt – cytosol, OVER – overrepresented and UNDER – underrepresented pathways.

Fig. 2

Mass-spectrometry analysis of the cytomatrix proteome. Pie charts illustrate (A) the structural proteome and (B) the enzyme spectrum of the HCT-15 cell cytomatrix. Proteins in the group were selected according to the intensity-based absolute quantification (iBAQ) score. The percentage for each group was calculated based on the total number of selected proteomes in each collection, which is shown within the slices.

Fig. 3

l-Lactate analysis of HCT-15 cell culture using LDH assay. HCT-15 cells were seeded in 24-well plates. After 48 h, growth medium was replaced with medium containing the indicated concentrations of compounds. 50 μL supernatant aliquots were transferred to 96-well plates at 10 and 20 h. Four replicates of supernatant in duplicate were each mixed with 50 μL of the LDH assay reaction mix. The mixture was then incubated for 2 h at room temperature in the dark, stopped by adding 50 μL of acetic acid. The absorbance was measured at 490 nm. The data represent the mean ± SD of four replicates. ∗∗∗p < 0.001 compared to untreated.

Fig. 4

Triggers of cancer. The cancer cycle includes genetic alterations (Step I), aerobic glycolysis (Step II), and heightened cytomatrix mechanics (Step III). The latter accelerates biochemical processes (Step IV), leading to biomass accumulation and cell size increases, which trigger cell division. The progression of the cycle can lead to tumor heterogeneity (Step IA). The absence of any cellular steps may inhibit tumor formation.