Netrin-1 as a potential target for metastatic cancer: focus on colorectal cancer.

Despite advanced screening technology and cancer treatments available today, metastasis remains an ongoing major cause of cancer-related deaths worldwide. Typically, colorectal cancer is one of the cancers treatable by surgery in conjunction with chemotherapy when it is detected at an early stage. However, it still ranks as the second highest modality and mortality of cancer types in western countries, and this is mostly due to a recurrence of metastatic colorectal cancer post-resection of the primary malignancy. Colorectal cancer metastases predominantly occur in the liver and lung, and yet the molecular mechanisms that regulate these organ-specific colorectal cancer metastases are largely unknown. Therefore, the identification of any critical molecule, which triggers malignancy in colorectal cancer, would be an excellent target for treatment. Netrin-1 was initially discovered as a chemotropic neuronal guidance molecule, and has been marked as a regulator for many cancers including colorectal cancer. Here, we summarise key findings of the role of netrin-1 intrinsic to colorectal cancer cells, extrinsic to the tumour microenvironment and angiogenesis, and consequently, we evaluate netrin-1 as a potential target molecule for metastasis.

Netrin-1-like-immunoreactivity Coexpresses With DCC and Has a Differential Level in the Myenteric Cholinergic and Nitrergic Neurons of the Adult Mouse Colon.

Netrin-1 is a potent axonal and neuronal guidance cue in the developing nervous system. Netrin-1 functions are mediated by its receptors, such as deleted in colorectal cancer (DCC) present on axons and neurons. Localization of DCC and Netrin-1 on various types of enteric neurons and their role in the mature enteric nervous system is unknown. The results of our study revealed that almost all enteric neurons and processes express DCC and Netrin-1 in the adult mice. Netrin-1-like-immunoreactivity (IR) was detected in the cytoplasm of neurons with some showing strong or weak staining. The majority of Netrin-1-like-immunoreactive enteric neurons were choline acetyltransferase (ChAT)-positive. However, ~19% of neurons were strongly Netrin-1-like-positive but ChAT-negative while ~8% of neurons were Netrin-1-like-negative but strongly ChAT-positive. In contrast, almost all nitric oxide synthase (nNOS)-positive enteric neurons displayed strong Netrin-1-like-IR. This differential intensity of Netrin-1 expression in the myenteric neurons might determine major neuronal subtypes regulating intestinal motility, ChAT-IR excitatory, and nNOS-IR inhibitory muscle motor and interneurons. This is the first study demonstrating the localization of DCC and Netrin-1 in the colonic myenteric plexus of the adult mice and their expression level determining two major neuronal subtypes regulating intestinal motility.

Netrin-1 in the developing enteric nervous system and colorectal cancer.

Netrin-1 is a well-characterised chemoattractant involved in neuronal guidance in the developing enteric nervous system (ENS), but it is also a regulator of tumorigenesis. Two of its well-characterised receptors, deleted in colorectal cancer (DCC) and uncoordinated-5 homolog (UNC-5H), belong to a family of dependence receptors that transmit either pro- or anti-apoptosis signals depending on the availability of ligand, in this case netrin-1. This review summarises these two effects of netrin-1 and highlights the additional research needed information about to allow better utilisation of netrin-1 as a therapeutic target for axonal regeneration in the context of colorectal cancer.