Abstract
Simple SummaryColorectal cancer accounts for approximately 10% of all annually diagnosed cancers worldwide being liver metastasis, the most common cause of death in patients with colorectal cancer. The interplay between tumor and stromal cells in the primary tumor microenvironment and at distant metastases are rising in importance as potential mechanisms of the tumor progression. In this review we discuss the new biomarkers derived from tumor microenvironment and liquid biopsy as emerging prognostic and treatments response markers for metastatic colorectal cancer. We also review the developing new clinical strategies based on tumor microenvironmental cells to tackle metastatic disease in metastatic colorectal cancer patients. Colorectal cancer (CRC) is one of the most common cancers in western countries. Its mortality rate varies greatly, depending on the stage of the disease. The main cause of CRC mortality is metastasis, which most commonly affects the liver. The role of tumor microenvironment in tumor initiation, progression and metastasis development has been widely studied. In this review we summarize the role of the tumor microenvironment in the liver pre-metastatic niche formation, paying attention to the distant cellular crosstalk mediated by exosomes. Moreover, and based on the prognostic and predictive capacity of alterations in the stromal compartment of tumors, we describe the role of tumor microenvironment cells and related liquid biopsy biomarkers in the delivery of precise medication for metastatic CRC. Finally, we evaluate the different clinical strategies to prevent and treat liver metastatic disease, based on the targeting of the tumor microenvironment. Specifically, targeting angiogenesis pathways and regulating immune response are two important research pipelines that are being widely developed and promise great benefits.
Highlights
In colorectal cancer (CRC), mortality rates vary widely, depending on the stage of the disease
Only rat sarcoma oncogene (RAS) mutation status is routinely used as a negative predictive marker to avoid treatment with anti-EGFR agents in patients with metastatic CRC (mCRC); and mismatch repair (MMR) status may guide the use of immune checkpoint inhibitors [36]
It is sometimes difficult to assess their specific origin, since they can be released by different cells, including tumor cells, exosomes released by tumor microenvironment cells and their cargo could be used as biomarker tools for oncology clinical practice in mCRC patients [128]
Summary
In colorectal cancer (CRC), mortality rates vary widely, depending on the stage of the disease. The main cause of CRC mortality is metastasis, with a five-year survival rate of approximately 10% for stage IV disease [1,2]. The process of metastasis requires invasion of a secondary tissue and cell growth. This process is relatively inefficient, as only 0.01% of circulating tumor cells cause successful metastasis [3]. In patients with metastatic CRC (mCRC), the liver is the most common site for metastasis. Around 20–30% of CRC patients present with hepatic metastasis at diagnosis, and. Primary CRC tumor location affects metastasis sites, with liver metastasis more common in left-sided CRC. Node, Metastases (TNM) stage at diagnosis [6]
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