CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment.

Yaoyao Zhang,Qingan Jia,Xia Liao,Arshad Ali,Binghui Xu

doi:10.3389/fgene.2021.649387

Abstract

The crosstalk between tumor cells and the tumor microenvironment (TME), triggers a variety of critical signaling pathways and promotes the malignant progression of cancer. The success rate of cancer therapy through targeting single molecule of this crosstalk may be extremely low, whereas co-targeting multiple components could be complicated design and likely to have more side effects. The six members of cellular communication network (CCN) family proteins are scaffolding proteins that may govern the TME, and several studies have shown targeted therapy of CCN family proteins may be effective for the treatment of cancer. CCN protein family shares similar structures, and they mutually reinforce and neutralize each other to serve various roles that are tightly regulated in a spatiotemporal manner by the TME. Here, we review the current knowledge on the structures and roles of CCN proteins in different types of cancer. We also analyze CCN mRNA expression, and reasons for its diverse relationship to prognosis in different cancers. In this review, we conclude that the discrepant functions of CCN proteins in different types of cancer are attributed to diverse TME and CCN truncated isoforms, and speculate that targeting CCN proteins to rebalance the TME could be a potent anti-cancer strategy.

Highlights

Cancer is the second leading cause of death in the United States and is becoming a major public health problem and central focus of modern medical research in China (Arbyn et al, 2020)
High expression of CCN1 was associated with shorter overall survival (OS) in five types of cancer [adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), brain lower grade glioma (LGG), mesothelioma (MESO), and stomach adenocarcinoma (STAD)] and longer OS only in skin cutaneous melanoma (SKCM), suggesting its role as a tumor suppressor
When we evaluated associations between CCN2 mRNA levels and prognosis, we found that high expression of CCN2 was associated with shorter OS in STAD and thyroid carcinoma (THCA) and longer OS only in SKCM, suggesting that it acts as a tumor suppressor

Summary

INTRODUCTION

Cancer is the second leading cause of death in the United States and is becoming a major public health problem and central focus of modern medical research in China (Arbyn et al, 2020). Owing to the signal peptide, CCN proteins are characteristically expressed in the cytoplasm and accumulate in the external environment in the form of paracrine Their four discrete functional domains determine the types of binding ligands with which they interact, including diverse integrins, HSPGs, IGFs, TGFβ, VEGF, and LRPs et al, resulting in a variety of biological functions of full-length CCN proteins (Perbal, 2004; Figure 1). In considering the interactions between the VWC domain in CCN proteins and TGF-β, BMP-4 et al, the CCN proteins could be a potential target for cancer therapy, while the specific roles are depended on the type and number of ligands in the TME. The final biological properties of the CCN proteins might be dependent on different combinations, and the cocktail containing CCN proteins in different combinations should be applied to rebalance the TME in tumor therapy

Functions and Progress of Truncated CCNs Associated With Cancer Progression

CCN Proteins Acting as Direct Modulators of Tumor Progression

Lung cancer

Melanoma Salivary gland tumors Oral squamous cell carcinoma

Endometrial cancer Laryngeal cancer

CONCLUSION AND PERSPECTIVES

Findings

AUTHOR CONTRIBUTIONS