Targeting the tumor stroma for cancer therapy

Abstract

Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.

Keywords: Clinical trial; Extracellular matrix; Mesenchymal stromal cells; Pericytes; Targeted therapy; Tumor stroma; cancer therapy; cancer-associated fibroblasts.

Fig. 1

Major components of the tumor stroma and their tumor-promoting functions

Fig. 2

A brief summary of CAFs functions and related mechanisms in cancer initiation and progression. Activated CAFs are involved in nearly all stadges of cancer development through diverse means. By releasing numerous secretory factors and activating signaling pathways, CAFs contribute to maliganant transformantion, tumor growth and proliferation, cancer cell invasion, and the establishment of pre-metaststic niche. These pro-tumorigenic cells also affect tumor metabolism in distinct manners as shown in the figure. All these functions collectively determain tumor development and drug resistance

Fig. 3

The tumor-promoting functions and related mechanisms of MSCs and TA-MSCs

Fig. 4

Interactions between stromal elements and each others

Fig. 5

Interactions between stromal cells and diverse immune cells

Fig. 6

Therapeutic approaches based on the stromal components