Abstract
Metastasis is the major cause of death in patients with colorectal carcinoma (CRC). The most common sites of metastasis are the liver and the peritoneum. Peritoneal carcinomatosis is often considered the end stage of the disease after the tumor has spread to the liver. However, almost half of CRC patients with peritoneal carcinomatosis do not present with liver metastasis. This brings up the question of whether peritoneal spread can still be considered as the end stage of a metastasized CRC or whether it should just be interpreted as a site of metastasis alternative to the liver. This review tries to discuss this question and summarize the current status of literature on potential characteristics in tumor biology in the primary tumor, i.e., factors (transcription factors and direct and indirect E-cadherin repressors) and pathways (WNT, TGF-β, and RAS) modulating EMT, regulation of EMT on a posttranscriptional and posttranslational level (miRNAs), and angiogenesis. In addition to tumor-specific characteristics, factors in the tumor microenvironment, immunological markers, ways of transport of tumor cells, and adhesion molecules appear to differ between hematogenous and peritoneal spread. Factors such as integrins and exosomal integrins, cancer stem cell phenotype, and miRNA expression appear to contribute in determining the metastatic route. We went through each step of the metastasis process comparing hematogenous to peritoneal spread. We identified differences with respect to organotropism, epithelial-mesenchymal transition, angiogenesis and inflammation, and tumor microenvironment which will be further elucidated in this review. A better understanding of the underlying mechanisms and contributing factors of metastasis development in CRC has huge relevance as it is the foundation to help find specific targets for treatment of CRC.
Highlights
Of all cancers, colorectal cancer (CRC) is the third most common with metastasis being the major cause of death in the majority of patients [1]
Metastases in the peritoneum are found in 25% of patients with an inferior prognosis when compared to other metastatic sites [4]
Peritoneal carcinomatosis is considered to be an advanced stage of CRC, in 41–45% of metastasized CRC patients it is the only site of metastatic disease suggesting that peritoneal spread might be a locally advanced form of CRC without other distant metastases [5, 6]. ese data point to the complexity of metastatic spread and many attempts have been made to understand the underlying principles of metastasis and organotropism. is review aims to give an overview of the current knowledge of the mechanisms of metastasis and metastatic organotropism in CRC
Summary
Colorectal cancer (CRC) is the third most common with metastasis being the major cause of death in the majority of patients [1]. Common sites of distant metastasis are the liver and the peritoneum. Peritoneal carcinomatosis is considered to be an advanced stage of CRC, in 41–45% of metastasized CRC patients it is the only site of metastatic disease suggesting that peritoneal spread might be a locally advanced form of CRC without other distant metastases [5, 6]. Ese data point to the complexity of metastatic spread and many attempts have been made to understand the underlying principles of metastasis and organotropism. Peritoneal carcinomatosis is considered to be an advanced stage of CRC, in 41–45% of metastasized CRC patients it is the only site of metastatic disease suggesting that peritoneal spread might be a locally advanced form of CRC without other distant metastases [5, 6]. ese data point to the complexity of metastatic spread and many attempts have been made to understand the underlying principles of metastasis and organotropism. is review aims to give an overview of the current knowledge of the mechanisms of metastasis and metastatic organotropism in CRC
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