Stromal cells in the tumor microenvironment: accomplices of tumor progression?

Abstract

The tumor microenvironment (TME) is made up of cells and extracellular matrix (non-cellular component), and cellular components include cancer cells and non-malignant cells such as immune cells and stromal cells. These three types of cells establish complex signals in the body and further influence tumor genesis, development, metastasis and participate in resistance to anti-tumor therapy. It has attracted scholars to study immune cells in TME due to the significant efficacy of immune checkpoint inhibitors (ICI) and chimeric antigen receptor T (CAR-T) in solid tumors and hematologic tumors. After more than 10 years of efforts, the role of immune cells in TME and the strategy of treating tumors based on immune cells have developed rapidly. Moreover, ICI have been recommended by guidelines as first- or second-line treatment strategies in a variety of tumors. At the same time, stromal cells is another major class of cellular components in TME, which also play a very important role in tumor metabolism, growth, metastasis, immune evasion and treatment resistance. Stromal cells can be recruited from neighboring non-cancerous host stromal cells and can also be formed by transdifferentiation from stromal cells to stromal cells or from tumor cells to stromal cells. Moreover, they participate in tumor genesis, development and drug resistance by secreting various factors and exosomes, participating in tumor angiogenesis and tumor metabolism, regulating the immune response in TME and extracellular matrix. However, with the deepening understanding of stromal cells, people found that stromal cells not only have the effect of promoting tumor but also can inhibit tumor in some cases. In this review, we will introduce the origin of stromal cells in TME as well as the role and specific mechanism of stromal cells in tumorigenesis and tumor development and strategies for treatment of tumors based on stromal cells. We will focus on tumor-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), tumor-associated adipocytes (CAAs), tumor endothelial cells (TECs) and pericytes (PCs) in stromal cells.

Fig. 1. The cellular components of solid tumors are composed of tumor cells, immune cells, and stromal cells, among which immune cells include: DC, NK, TAM, TAN, MDSC, CD4⁺T cell/ CD8⁺T cell/Treg, and Breg.

Stromal cells include CAF, MSC, CAA, TEC, and PC. These three types of cells establish complex signaling pathways that affect tumor occurrence, tumor progression, and tumor resistance to treatment. Dendritic cell: DC; Natural killer cell: NK; M1/M2 tumor-associated macrophage: M1/M2 TAM; N1/N2 tumor-associated neutrophil: N1/N2 TAN; Myeloid-derived suppressor cell: MDSC; CD4⁺T lymphocyte/CD8⁺T lymphocyte/regulatory T cell: CD4⁺T cell/CD8⁺T cell/Treg; Regulatory B cell: Breg; Tumor-associated fibroblast: CAF; Mesenchymal stem cell: MSC; Tumor-associated adipocyte: CAA; Tumor endothelial cell: TECs; Pericyte: PC.

Fig. 2. The mechanism of cancer-associated fibroblasts (CAFs) promoting tumor growth.

CAFs can promote tumor growth through a variety of mechanisms: such as secreting a variety of cytokines; reshaping the extracellular matrix (ECM); promoting angiogenesis; inhibiting anti-tumor immune cells, providing metabolites (such as lactic acid, amino acids, fatty acids) to tumor cells; and participating in resistance to anti-tumor treatment, etc.

Fig. 3. Mesenchymal stem cells (MSCs) promote tumor progression through multiple mechanisms and multiple pathways, among which signaling pathways include: PI3K/AKT pathway, Hippo pathway, MYC pathway, JAK/STAT pathway, NF-κB pathway, etc.

The mechanisms include: cell-to-cell contact, secretion of cytokines and exosomes, inhibition of immune cells activity, promotion of angiogenesis, promotion of epithelial interstitial transformation (EMT), transforming into cancer-associated fibroblasts (CAFs), etc, and ultimately promote cancer cells proliferation, tumor metastasis and anti-tumor treatments.

Fig. 4. Complex relationship between tumors and cancer-associated adipocytes (CAAs): tumors induce the formation of CAAs by adipocytes/mesenchymal stem cells (MSCs)/cancer stem cells (CSCs) by secreting soluble factors tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), plasminogen activator inhibitor 1, Wnt3a, and exosomes.

Activated CAAs showed a decrease in adipocyte markers such as adipocytes/macrophage fatty acid-binding protein 2 (Ap2) and fatty acid-binding protein 4 (FABP4), while the expression of MMP11 and the release of IL-6, IL-1β, and IGFBP-2 increased. CAAs secrete cytokines, adipokines, lipid metabolites, and exosomes to promote the proliferation of cancer cells, regulate extracellular matrix (ECM) structure, form an immunosuppressive microenvironment, promote tumor angiogenesis and epithelial interstitial transformation (EMT), and ultimately promote tumor growth, metastasis and resistance to anti-tumor treatment.

Fig. 5. Possible mechanisms of tumor endothelial cells (TECs) abnormalities.

TECs can be formed by transdifferentiation of tumor cells, cancer stem cells (CSCs), or vascular progenitor cells (VPCs), and TECs can also be formed by fusion of normal endothelial cells (NECs) with malignant tumor cells or VPCs. TECs can also absorb apoptotic bodies or exosomes released by tumor cells, which can absorb tumor oncogenes. In addition, growth factors or cytokines in the tumor microenvironment can lead to genetic instability of TECs, thereby leading to TECs abnormalities.

Fig. 6. The immunoregulation of pericyte in the tumor microenvironment: Pericytes (PCs) can recruit tumor-associated macrophages (TAMs) by releasing IL-33, CXCL12, etc.

PCs can induce the expression of IL-6 thereby increasing the migration of bone marrow-derived suppressor cells (MDSCs). PC can also increase the recruitment of regulatory T cells (Treg) and B cells. Not only that, PCs may be an inhibitor of CD8⁺ T cells infiltration. It is also a negative regulator of CD4⁺ T cells, inducing the incompetence of CD4⁺ T cells. PCs can also inhibit T cells proliferation by releasing PGE2, NO, HGF, etc.