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Abstract
Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis (LM) cascade is known in the literature, its mechanisms are still unclear and remain studied in different research models. A connection is suggested between nervous system dysfunctions and a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), Neurotrophins (Ntt) and their receptors (Rs) in CRC liver metastasis development. Studies on the role of NP/NP-Rs in the progression and metastasis of CRC, show the complexity of brain–tumor interactions, caused by their different forms of release to the extracellular environment (endocrine, autocrine, paracrine and neurocrine). Many stages of LM are connected to the activity of pro-inflammatory, e.g., Corticotropin-releasing Hormone Receptor 1 (CRHR1), Neuropeptide Y (NPY) and Neurotensin (NT), anti-inflammatory, e.g., Calcitonin Gene-related Peptide (CGRP), CRHR2 and Vasoactive Intestinal Polypeptide (VIP) or dual role neuropeptides, e.g., Substance P (SP). The regulation of the local immunological profile (e.g., CRH/CRHRs), dysfunctions of enteroprotective role of NPs on epithelial cells (e.g., NT/NT-R), as well as structural-functional changes in enteric nervous system innervation of the tumor are also important. More research is needed to understand the exact mechanisms of communication between the neurons and tumor cells. The knowledge on the mechanisms regulating tumor growth and different stages of metastasis, as well as effects of the action of a numerous group of Nts/NPs/Ntt as growth factors, have implications for future therapeutic strategies. To obtain the best treatment outcomes, it is important to use signaling pathways common for many NPs, as well to develop a range of broad-spectrum antagonists. This review aims to summarize the current knowledge on the importance of neuroactive molecules in the promotion of the invasion-metastasis cascade in CRC, as well as the improvements of clinical management of CRC liver metastasis.
Highlights
Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, after lung and breast/prostate cancer, is the second leading cause of cancer-associated death [1,2]
From the studied group of NPs/NP receptors (NP-Rs), some were overexpressed in primary CRC (pCRC) tissues compared with control, which might be linked to liver metastases
When it comes to the research on TrK tissue expression in CRC, the results are consistent for correlation of expression of these receptors with lymph node and peritoneal metastases, with less consistency when it comes to correlation with liver metastases (LM)
Summary
Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, after lung and breast/prostate cancer, is the second leading cause of cancer-associated death [1,2]. Liver metastases are more often associated with commonly recognized CRC risk factors, such as sex (more prevalent in men), age (more common in women over 70 years of age, as compared to younger) [7], diabetes [24], high levels of low-density cholesterol (LDL) and LDL receptor (LDLR) [25] or alcohol consumption [26]. A strong connection is suggested between brain–gut axis dysfunctions, the expression of a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), as well as Nerve Growth Factor (NGF) family of proteins called Neurotrophins (Ntt) and the progression of CRC (including distant metastases) [17,18,28,29,30]. CRC was chosen for the analysis, as in this cancer, LM is the most common cause of death, while the involvement of nerve dysfunctions accompanying CRC, as well as the role of the complex NP system in LM, still seems to be relatively poorly described
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