Overexpression of miR-221 and miR-222 in the cancer stroma is associated with malignant potential in colorectal cancer
Colorectal cancer (CRC), bowel cancer, is the fourth most commonly diagnosed cancer in both the UK and USA. It is the second leading cause of cancer death accounting for 16,000 deaths in the UK and over 50,000 deaths in the US.
25% of patients are diagnosed with metastatic disease already present and 50% of CRC patients will develop liver metastases. The prognosis for patients with metastatic CRC is very poor with a 5 year survival rate of less than 10%.
Recently, studies have focussed on the role of the tumour microenvironment in cancer progression. Stromal cells have been implicated in tumour and metastatic progression via secreted growth factors, chemokines and cytokines. Another mechanism of tumour/stromal cell interaction has been suggested by microRNA present in the extracellular matrix that can influence both stromal and tumour cells.
In this study Iida et al. investigated the role of stromal miRNA in patients with metastatic cancer, aiming to identify those miRNAs present in the stroma that may contribute to metastases.
The authors used RNA from laser capture microdissected tissue resected from CRC patients to conduct an miRNA microarray. They used qRT-PCR to validate these results followed by miRNA in situ hybridisation to investigate the localisation of interesting targets.
Using the Toray 3D‑Gene Human miRNA Oligo chips ver. 19, Iida et al. identified 27 miRNAs associated with stroma in CRC patients with liver metastases but not CRC tissue without.
Four of these miRNAs were downregulated (miR-659, -4470, -4669 and -5703) and two were upregulated (miR-221 and miR-222).
This was validated by qRT-PCR on 20 further independent samples from CRC patients with and without liver metastases. The four downregulated miRNAs (miR-659, -4470, -4669 and -5703) were not significantly different but miR-221 and miR-222 were overexpressed in CRC tissue containing liver metastases.
miR-221 and miR-222 were further analysed by qRT-PCR on FFPE tissue from 101 primary CRC samples. Patients where stromal miR-221 was expressed at levels higher than the median had more severe pathologies including venous invasion, liver metastases and distant metastases.
Similarly miR-222 was associated with more advanced liver metastases and distant metastases and also increased depth invasion of tumours.
These associations were not observed when miR-221 and miR-222 were overexpressed in the cancer cells, only when overexpressed in the stromal cells.
Statistical analysis of the CRC cohort revealed that both miR-221 and miR-222 were independent markers of poor overall survival rates of patients with CRC. Higher pathological T stage and lymph node metastases were also independent markers.
Analysis of CRC tissue with locked nucleic acid in situ hybridisation revealed expression of miR‑221 and miR‑222 in the cytoplasm of fibroblasts in stromal tissue and cancer cells of CRC patients with liver metastases. In CRC tissue without liver metastases only low expression of both miRs was observed.
In this study the authors demonstrated expression of miRs in the cancer associated stroma of CRC patients with liver metastases. They speculate that miRs expressed in tumour tissue may be transferred via exosomes to fibroblasts altering their phenotype to that of cancer associated fibroblasts (CAFs). They further suggest that this may influence the function of these cells promoting tumour invasion and metastatic potential.
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