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

Fuhr Fuhr,El-Athman El-Athman,Carbone Carbone,Abreu Abreu,Relógio Relógio,Bianchi Bianchi,Laukkanen Laukkanen,Mazzoccoli Mazzoccoli

doi:10.3390/cancers11070988

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.

Highlights

Colorectal cancer (CRC) ranks the fourth leading cause of cancer deaths and the third most commonly diagnosed malignant neoplastic disease [1,2,3]
These translational feedback loops (TTFLs) are mainly driven by the heterodimer complex formed by the proteins BMAL1/ BMAL2 and CLOCK/NPAS2, which activate the transcription of PERIOD (PER1-3), CRYPTOCHROME (CRY1-2), REV-ERB (REV-ERB1, REV-ERB2), and ROR (RORa, RORb, RORc) genes and their corresponding proteins that fine-tune the transcriptional activity of BMAL1/2-CLOCK/NPAS2 heterodimers [14,15]
We accessed the expression patterns of the core-clock genes, as well as the metabolic and phenotypic characteristics of colon cancer cells upon interaction with stromal cells. We explored this cross-talk using co-cultures of colon cancer cells (HCT116) and a commercial line of normal human intestinal fibroblasts (HIFs), as well as primary normal fibroblasts (NFs) and primary tumour-associated fibroblasts (TAFs) derived from specimens obtained from CRC patients

Summary

Introduction

Colorectal cancer (CRC) ranks the fourth leading cause of cancer deaths and the third most commonly diagnosed malignant neoplastic disease [1,2,3]. The tumour microenvironment seems to play a crucial role in CRC progression, metastasis, and drug resistance It consists of an extracellular matrix, tumour-associated fibroblasts (TAFs) able to uphold carcinogenesis and dwindle drug sensitivity, activated immune cells, and tumour vasculature [6]. The biological clock drives crucial cellular processes, such as the cell division cycle, metabolism, proliferation, DNA damage response, apoptosis, and autophagy, which when altered are critical in cancer onset and progression [16,17,18,19,20]. Altered expression of PER genes was found in non-small lung cancer patients [21], as well as in breast cancer patients In the latter neoplastic disease PER1-3 downregulation predicted poorer survival [22].

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