Abstract
Peritoneal infection after colorectal cancer surgery is associated with a higher rate of tumor relapse. We have recently proposed that soluble inflammatory factors released in response to a postoperative infection enhance tumor progression features in residual tumor cells. In an effort to set up models to study the mechanisms of residual tumor cell activation during surgery-associated inflammation, we have analyzed the phenotypic response of colon cancer cell lines to the paracrine effects of THP-1 and U937 differentiated human macrophages, which release an inflammatory medium characteristic of an innate immune response. The exposure of the colon cancer cell lines HT-29 and SW620 to conditioned media isolated from differentiated THP-1 and U937 macrophages induced a mesenchymal-like phenotypic shift, involving the activation of in vitro invasiveness. The inflammatory media activated the β-catenin/TCF4 transcriptional pathway and induced the expression of several mesenchymal (e.g., FN1 and VIM) and TCF4 target genes (e.g., MMP7, PTGS2, MET, and CCD1). Similarly, differential expression of some transcription factors involved in epithelial-to-mesenchymal transitions (i.e. ZEB1, SNAI1, and SNAI2) was variably observed in the colon cancer cell lines when exposed to the inflammatory media. THP-1 and U937 macrophages, which displayed characteristics of M1 differentiation, overexpressed some cytokines previously shown to be induced in colorectal cancer patients with increased rates of tumor recurrence associated with postoperative peritoneal infections, thus suggesting their pro-tumoral character. Therefore, the environment created by inflammatory M1 macrophages enhances features of epithelial-to-mesenchymal transition, and may be useful as a model to characterize pro-inflammatory cytokines as putative biomarkers of tumor recurrence risk.
Highlights
Surgery is at present the only treatment with curative intent for patients with colorectal cancer (CRC) [1]
We searched for macrophagic cell lines with features characteristic of an innate immune response to set up in vitro models that reproduce the mechanisms of tumor progression driven by inflammatory processes–e.g. peritoneal infections after colorectal cancer surgery
Treatment of the colon cancer cell lines HT-29 and SW620 with conditioned media from PMA-differentiated THP-1 or U937 macrophages (MACRO-CM) led to a dramatic change in the cell phenotype compared to treatment with conditioned media from non-differentiated monocytic cells (MONO-CM) or control media (CON)
Summary
Surgery is at present the only treatment with curative intent for patients with colorectal cancer (CRC) [1]. Still, operated CRC recurs in up to 40% of patients despite complete resection of the tumor. Anastomotic leakage after CRC surgery occurs at a frequency between 3 to over 15%, depending mostly on the tumor location [6]. Several studies have shown that the anastomotic leakage and subsequent intra-abdominal infections are associated with higher rates of tumor recurrence and cancer-specific mortality [7,8,9,10,11,12,13,14,15,16,17]. The severity of the postoperative infection has been correlated with the increased risk of recurrence [17, 18]
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