Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications

Abstract

A high expression of the phosphoprotein osteopontin (OPN) has been associated with cancer progression in several tumor types, including breast cancer, hepatocarcinoma, ovarian cancer, and colorectal cancer (CRC). Interestingly, OPN is overexpressed in CRC and is associated with a poor prognosis linked to invasion and metastasis. Here, we review the regulation and functions of OPN with an emphasis on CRC. We examine how epigenetic and genetic regulators interact with the key signaling pathways involved in this disease. Then, we describe the role of OPN in cancer progression, including proliferation, survival, migration, invasion, and angiogenesis. Furthermore, we outline the interest of using OPN as a clinical biomarker, and discuss if and how osteopontin can be implemented as a routine assay in clinical laboratories for monitoring CRC patients. Finally, we discuss the use of OPN an attractive, but challenging, therapeutic target.

Keywords: biomarker; colorectal cancer (CRC); metastasis; osteopontin; therapeutic target.

Figure 1

Epigenetic and genetic regulation of the OPN promoter in CRC. The regulation of the osteopontin expression is complex and involves both genetic and epigenetic mechanisms such as promoter methylation, as well as different protein complexes acting on the histones and thereby regulating the compaction of chromatin within the SIBLING gene cluster. The osteopontin promoter also contains numerous binding sites for transcription factors that act in coordination to regulate the transcriptional activity. Some are known to be connected to important CRC signaling pathways, particularly the Wnt pathway, as well as the TGFβ pathway and the Hedgehog pathway. The pre-messenger is also subject to alternative splicing generating different isoforms and contains an alternative initiation site leading to the formation of a shorter protein. Osteopontin may be intracellular (nucleus, cytoplasm, and secretory vesicle) or extracellular following secretion. Osteopontin is believed to play a role in the liver both as a matrix protein and as a cytokine mediating signaling between tumor cells, as well as between cells in the tumor environment, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), which also secrete osteopontin.

Figure 2

Role of OPN in CRC progression. OPN is involved in cancer progression by regulating various aspects of tumor progression and metastasis, including (1) increased proliferation and cell growth, (2) decreased cell death, (3) increased migration and invasion, (4) neo-angiogenesis, (5) promotion of the epithelial-mesenchymal transition (EMT), (6) increased stemness and drug resistance, (7) modulation of immunity and inflammation both at the primary and metastatic sites, (8) intravasation and survival of circulating tumor cells (CTC), and (9) promotion of liver metastasis. sOPN—secreted OPN; iOPN—intranuclear OPN; MET—mesenchymal to epithelial transition; HRE—HIF response element.