Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance

Abstract

Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.

How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells

“…The TME in CRC is a physical shelter for CSC[ 5 ] composed of biomolecules from the extracellular matrix, an aberrant vasculature and multiple stromal and immune cell types. These cells include mesenchymal stem cells, cancer-associated fibroblasts (CAFs), endothelial cells (ECs), pericytes, and tumor infiltrating immune cells which comprehend: Macrophages, neutrophils, natural killer cells, Treg cells and cytotoxic T lymphocytes[ 2 , 4 ]. The interaction between CRC cells and the different types of cellular and non-cellular elements of TME involves complex and dynamic crosstalk by paracrine signaling[ 22 ].…”

“…However, this disease remains the third most prevalent type of cancer, having an incidence of 10% and ranking second in mortality (9.4% among all cancer deaths) according to global cancer statistics[ 3 ]. The leading cause of patient deaths and relapses is the appearance of new CRC subtypes and the acquired resistance to currently used therapies[ 4 ]. Moreover, a great number of CRC are diagnosed with distal metastases and these patients have a poor survival rate due to a lack of response to therapy[ 2 ].…”

“…Together these components constitute the tumor microenvironment (TME). In the last decades, several investigations have demonstrated that tumor surrounding ambiance through its proinflammatory role, among others, actively participates in the development, progression and chemoresistance of CRC[ 1 , 4 ].…”

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

“…3 The Wnt/β-catenin pathway is a vital cellular signaling cascade regulating various embryonic developmental processes, tissue homeostasis, 4 self-renewal, and differentiation of cancer stem cells. 5 Abnormally activated Wnt/β-catenin signaling is a risk factor for the development of multiple malignancies, particularly CRC, and it has important therapeutic implications. 6 Therefore, the function of the Wnt/βcatenin signaling axis in both hereditary and sporadic CRC is always the focus of intensive research.…”

“…However, without the Wnt ligand, β-catenin is degraded in the cytoplasm by a complex that is composed of Axin, adenomatosis polyposis coli (APC), glycogen synthase kinase-3 beta (GSK-3β), and casein kinase 1α (CK1α) . The Wnt/β-catenin pathway is a vital cellular signaling cascade regulating various embryonic developmental processes, tissue homeostasis, self-renewal, and differentiation of cancer stem cells . Abnormally activated Wnt/β-catenin signaling is a risk factor for the development of multiple malignancies, particularly CRC, and it has important therapeutic implications .…”