The Interplay between Colon Cancer Cells and Tumour-Associated Stromal Cells Impacts the Biological Clock and Enhances Malignant Phenotypes

Abstract

Cancer cells interrelate with the bordering host microenvironment that encompasses the extracellular matrix and a nontumour cellular component comprising fibroblasts and immune-competent cells. The tumour microenvironment modulates cancer onset and progression, but the molecular factors managing this interaction are not fully understood. Malignant transformation of a benign tumour is among the first crucial events in colorectal carcinogenesis. The role of tumour stroma fibroblasts is well-described in cancer, but less well-characterized in benign tumours. In the current work we utilized fibroblasts isolated from tubulovillous adenoma, which has high risk for malignant transformation, to study the interaction between benign tumour stroma and the circadian clock machinery. We explored the role of the biological clock in this interplay taking advantage of an experimental model, represented by the co-culture of colon cancer cells with normal fibroblasts or tumour-associated fibroblasts, isolated from human colorectal tumour specimens. When co-cultured with tumour-associated fibroblasts, colon cancer cells showed alterations in their circadian and metabolic parameters, with decreased apoptosis, increased colon cancer cell viability, and increased resistance to chemotherapeutic agents. In conclusion, the interactions among colon cancer cells and tumour-associated fibroblasts affect the molecular clockwork and seem to aggravate malignant cell phenotypes, suggesting a detrimental effect of this interplay on cancer dynamics.

The Core-Clock Gene NR1D1 Impacts Cell Motility In Vitro and Invasiveness in a Zebrafish Xenograft Colon Cancer Model

“…In addition to the modelling approach, the data from our spheroid assay indicates that the 3D architecture of cells in the host may have an impact on the reduced cell proliferation observed in vivo and offer an alternative explanation for the observed phenotype ( Figure 4P). Altogether, our data highlights a profound role for tumour microenvironment in affecting cancer behaviour in terms of proliferation, apoptosis and metastatic potential, likely due to the cancer/host circadian clock interplay, as seen previously using co-culture experiments with colon cancer cells [35]. Our work highlights the different functionalities of the colon cancer circadian clock as a function of their environmental conditions (in vitro vs. in vivo), and their implications on the cancer phenotype.…”

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…High throughput metabolic profiling by Seahorse extracellular flux assays made it possible to observe differences between quiescent, activated, and memory immune cells [425][426][427], evaluate the effects of changes in the cellular microenvironment [428][429][430],…”

The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer

“…The idea that the tumor microenvironment can disrupt circadian oscillation is supported by a study showing that healthy skin cells adjacent to a cutaneous melanoma had significantly reduced expression of clock genes [111]. Coculture experiments showed that the cancer cells circadian phenotype, metabolism and survival are affected by surrounding cells [112]. This implies something in the surrounding environment is disrupting the clocks of healthy cells, whether it is through hypoxia, acidosis or secreted factors.…”