Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process.

Naofumi Mukaida,Di Zhang,So-Ichiro Sasaki

doi:10.3390/cancers12102896

Abstract

Simple SummaryBone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs their prognosis. Bone metastasis proceeds through the interaction between cancer cells and resident cells in bone. Among resident cells, osteoclasts are commonly activated in bone metastasis, and therefore, the drugs targeting osteoclast activation are frequently used to treat bone metastasis. However, their ineffectiveness to inhibit cancer cell growth in bone marrow, raises the possibility of the involvement of additional types of resident cells in bone metastasis. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues as well as metastatic organs including bone. Hence, we will discuss the potential roles of CAFs, which are emerging as an important cellular player in bone metastasis.Bone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs patients’ quality of life and prognosis. At the first step of bone metastasis, cancer cells adhere to the endothelium in bone marrow and survive in a dormant state by utilizing hematopoietic niches present therein. Once a dormant stage is disturbed, cancer cells grow through the interaction with various bone marrow resident cells, particularly osteoclasts and osteoblasts. Consequently, osteoclast activation is a hallmark of bone metastasis. As a consequence, the drugs targeting osteoclast activation are frequently used to treat bone metastasis but are not effective to inhibit cancer cell growth in bone marrow. Thus, additional types of resident cells are presumed to contribute to cancer cell growth in bone metastasis sites. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues and can have diverse roles in cancer progression and metastasis. Given the presence of CAFs in bone metastasis sites, CAFs are emerging as an important cellular player in bone metastasis. Hence, in this review, we will discuss the potential roles of CAFs in tumor progression, particularly bone metastasis.

Highlights

Various types of solid tumors, breast, prostate and lung cancer, frequently metastasize to bone during their course and the bone is the third commonest site of metastasis after the liver and lung [1]
We discussed the potential contribution of Cancer-associated fibroblasts (CAFs) in bone marrow to bone metastasis
Overt bone metastasis was seldom seen in several types of cancers, such as gastric, colorectal, pancreatic, and cervical cancer, which occasionally harbor tumor cells in bone marrow [121,122]

Summary

Introduction

Various types of solid tumors, breast, prostate and lung cancer, frequently metastasize to bone during their course and the bone is the third commonest site of metastasis after the liver and lung [1]. Activated fibroblasts in wound healing sites, display a contractile phenotype with enhanced expression of α-smooth muscle actin (α-SMA) and are referred to as myofibroblasts. Like myofibroblasts in wound healing sites, CAFs can produce a wide variety of growth factors, cytokines, and chemokines. Based on these properties, it is widely accepted that CAFs have diverse and profound impacts on tumor growth, at its primary site, but lack of a specific marker has hindered a clear-cut understanding of their roles, at metastatic sites. After summarizing the origin and functions of CAFs, we will discuss the roles of CAFs in bone metastasis, together with the incorporation of fibroblast-related cells and MSCs into consideration

Phenotypes and Origins of Fibroblasts and CAFs

Bone Metastasis Process

CAFs in Bone Metastasis Formation

Conclusions and Future Perspective