The Multiple Roles and Therapeutic Potential of Clusterin in Non-Small-Cell Lung Cancer

A Narrative Review

Juofang Tan; Wei Guo; Su Yang; Dingpei Han; Hecheng Li

Disclosures

Transl Lung Cancer Res. 2021;10(6):2683-2697. 

In This Article

Abstract and Introduction

Abstract

Worldwide, lung cancer is the most common form of cancer, with an estimated 2.09 million new cases and 1.76 million of death cause in 2018. It is categorized into two subtypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Although platinum-based chemotherapy or molecular targeted drugs is recommended for advanced stages of NSCLC patients, however, resistance to drug and chemotherapy are hindrances for patients to fully beneficial from these treatments. Clusterin (CLU), also known as apolipoprotein J, is a versatile chaperone molecule which produced by a wide array of tissues and found in most biologic fluids. There are studies reported high expression of CLU confers resistance to chemotherapy and radiotherapy in different lung cancer cell lines. By silencing CLU using Custirsen (OGX-011), a second-generation antisense oligonucleotide (ASO) that inhibits CLU production, not only could sensitized cells to chemo- and radiotherapy, also could decreased their metastatic potential. We will review here the extensive literature linking CLU to NSCLC, update the current state of research on CLU for better understanding of this unique protein and the development of more effective anti- CLU treatment.

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide, incidence and mortality rates of lung cancer have been ballooning in recent years. The etiologic factors of lung cancer have become more complex along with environmental pollution, urbanization, and industrialization problems around the world. In 2018, it is estimated that 2.09 million new cases of lung cancer (11.6% of total cancer cases) and 1.76 million of death cause by lung cancer (18.4% of total cancer death) occurred all over the world, ranking first in the most frequent cancer and cause of cancer death among all cancer types, in combined of men and women.[1] The American Cancer Society's estimates that fresh cases of lung cancer in the United States for 2020 are about 228,820 (116,300 in men and 112,520 in women) and 135,720 deaths from lung cancer in 2020 (72,500 in men and 63,220 in women).[2]

Histologically, lung cancer could be categorized into two subtypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). The World Health Organization (WHO) has classified NSCLC into adenocarcinoma, squamous cell carcinoma and large cell carcinoma.[3] Surgery is still recommended for patients with early stages of NSCLC, while platinum-based chemotherapy or molecular targeted drugs remains the first-line treatment for advanced stages.[4] However, the 5-year survival rate is still considered low (<7%).[5] SCLC, accounts for approximately 14% of all lung cancers, highly metastatic and rapid growth contribute SCLC to a high mortality rate and low survival rate, most patients survive for only a year or less.[6] Thus, it is rarely possible for surgical resection, chemotherapy and/or radiotherapy became the remaining options. Although the combination of radiotherapy with either surgery or chemotherapy treatment proven could improve the survival of SCLC patients,[7,8] still, the general 5-year survival rate of people with SCLC patients is 6%.[5]

Clusterin (CLU), also known as apolipoprotein J, testosterone-repressed prostate message-2 (TPRM-2), sulphated glycoprotein-2 (SGP-2) and compliment lysis inhibitor (CLI), was first isolated from ram rete testes fluid in 1986, they showed that a heat-stable, trypsin sensitive protein was responsible to aggregate cells, so they named this extracellular cell 'Clusterin'.[9] CLU is a highly conserved glycoprotein found nearly ubiquitous in tissues and body fluids.[10] In human, CLU was described as CLI in 1989 firstly, a component of soluble terminal complement complexes immunologically identified in human seminal plasma, playing an important role in protecting sperm cells and epithelial tissues against complement attack in the male reproductive system.[11] Since then, CLU has been found implicated in many processes, which included apoptosis, cell cycle regulation and DNA repair.[12–16]

Several studies have reported high expression of CLU in different lung cancer cell lines.[17,18] Compared to normal lung cancer cells, CLU expression was found higher in drug-resistant lung cancer cell lines, which indicates that CLU might be involved in drug resistant. Moreover, CLU could also represent an independent prognostic factor in surgically resected lung cancer patients.[19,20]

In this review, we will firstly discuss the structure and physiology function of CLU, then about the role of CLU in tumorigenesis, metastasis, chemotherapy and radiotherapy in lung cancer.

The information used to write this review was collected from PUBMED database (date of the last search 14 March 2021), using combinations of search terms including "lung cancer", "clusterin", "apolipoprotein J", "chemotherapy", "radiotherapy" and "antisense oligonucleotide". Reference lists of identified articles were searched manually to find other relevant studies. We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/tlcr-20-1298.

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