ABSTRACT
According to the seed and soil theory, also known as the Paget’s hypothesis, the tumor microenvironment (TME) plays a key role in promoting the onset and progression of cancer. In particular, fibroblasts and macrophages of the TME have been shown to regulate virtually all key tumor characteristics, from invasion to metastasis and resistance to therapy. There are numerous molecules that confer protumorigenic properties to the cells of the TME. The aim of this study was to analyze in a series of colorectal cancers the expression of the L1 cell adhesion molecule (L1CAM) in the cells of the TME, in order to better clarify the role of these cells in colorectal cancer (CRC) onset and progression. In the present study, 48 patients with CRC, aged between 38 and 88 years, were analyzed. L1CAM expression in the cells of the TME was detected in 35/48 cases (73%). L1CAM expression did not always parallel immunostaining for the adhesion molecule in tumor cells. Four groups were identified: group 1, stromal cells+/Tumor- (15/48 cases); group 2, stromal cells-/Tumor+ (19/48 cases); group 3, stromal cells+/Tumor+ (20/48 cases); group 4, stromal cells-/Tumor- (3/48 cases). Immunostaining of L1CAM-positive stromal cells of the TME with CD163 and alpha-SMA showed that both macrophages (CD163-positive) and fibroblasts (alpha-SMA-positive) were involved in L1CAM expression. L1CAM expression in stromal cells was also associated with the acquisition of a motile phenotype by tumor cells: among 20 CRCs with budding margins, 17 (85%) were characterized by L1CAM expression in peritumoral infiltrating cells. In this study, L1CAM expression in the peritumoral stroma was not limited to stromal cells, being also expressed in cells of the enteric nervous system. The strong immunoreactivity of neural structures for L1CAM allowed a better identification of perineural invasion in CRC. According to our preliminary results, the study of L1CAM expression in the peritumoral infiltrating cells in CRC patients could represent a valid tool able to stratify patients with colorectal cancer regarding the possible occurrence of metastasis and recurrence.

IMPACT STATEMENT
The positivity of L1CAM in patients with CRC and in CAF as well as 62 a valid help to stratify patients for the possible onset of metastases and recurrences 63 could be a valid study potential for improving the therapeutic approach.