Cancer-associated fibroblasts and the tumor microenvironment in non-small cell lung cancer

ABSTRACT

Introduction

Non-small cell lung cancer (NSCLC) has a markedly poor prognosis as it progresses, and the prognosis is still unsatisfactory even with modern treatments. Cancer is composed of not only cancer cells, but also stroma consisting of various cell types. Cancer-associated fibroblasts (CAFs) are a major component of the stroma and the associated tumor microenvironment (TME). Particularly, CAFs are a critical component in elucidating the biological mechanisms of cancer progression and new therapeutic targets. This article outlines the TME formed by CAFs in NSCLC.

Areas covered

Focusing on the TME in NSCLC, we discuss the mechanisms by which CAFs are involved in cancer progression, drug resistance, and the development of therapies targeting CAFs.

Expert opinion

In the TME, CAFs profoundly contribute to tumor progression by interacting with cancer cells through direct contact or paracrine cytokine signaling. CAFs also interact with various other stromal components to establish a tumor-promoting immunosuppressive microenvironment and remodel the extracellular matrix. Furthermore, these effects are closely associated with drug resistance. Further elucidation of the stromal microenvironment, including CAFs, could prove to be crucial in the treatment of NSCLC.

KEYWORDS:

• Non-small cell lung cancer
• stroma
• cancer-associated fibroblast
• microenvironment
• immune microenvironment
• tumor-infiltrating lymphocytes
• tumor-associated macrophages
• drug resistance

Article highlights

• The components of tumor tissue include cancer cells and stroma. The stroma is composed of a variety of diverse cells and materials, forming a tumor microenvironment (TME) that is conducive to tumor development. Cancer-associated fibroblasts (CAFs) are a major component of the stroma and have long been studied as a major contributor to the TME.

• CAFs are a heterogeneous cell population of various origins. Although markers for CAFs, such as α-SMA and FAP, are well known, they are not specific to CAFs. This lack of specificity has made the definition and identification of CAFs extremely challenging.

• CAFs contribute to the development of a tumor-promoting microenvironment by interacting with cancer cells and other stromal cells through extracellular matrix remodeling, secretion of various cytokines, direct contact, and exosomes.

• The various interactions between CAFs, cancer cells, and other stromal components have also been implicated in the observed resistance to anticancer drugs and molecularly targeted agents.

Although no clinically effective drugs have been developed, several ongoing studies are developing cancer treatments based on the inhibition of factors involved in the activation of CAFs and their interaction with other cells of the TME.

Conflict of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

M Tsuboi has received grants or contracts from Boehringer-lngelheim Japan, MSD, AstraZeneca KK, ONO Pharmaceutical Co., Ltd, MSD, Bristol-Myers Squibb KK and commissioned research fo Eli Lilly Japan. M Tsuboi has received consulting fees from AstraZeneca KK, Chugai Pharmaceutical Co., Ltd, MSD and received advisory and consultancy feed from Novartis.

M Tsuboi has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co., Ltd, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical Co., Ltd, MSD, Bristol-Myers Squibb KK and received lecture fees and honoraria from Teijin Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper received no funding.