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Review
. 2021 Nov 25;13(23):5917.
doi: 10.3390/cancers13235917.

Propensity for Early Metastatic Spread in Breast Cancer: Role of Tumor Vascularization Features and Tumor Immune Infiltrate

Mario Rosario D'Andrea  1 , Vittore Cereda  1 , Luigi Coppola  2 , Guido Giordano  3 , Andrea Remo  4 , Elena De Santis  5
Affiliations
Review

Propensity for Early Metastatic Spread in Breast Cancer: Role of Tumor Vascularization Features and Tumor Immune Infiltrate

Mario Rosario D'Andrea et al. Cancers (Basel). .

Abstract

Breast cancer is a complex and highly heterogeneous disease consisting of various subtypes. It is classified into human epidermal growth receptor 2 (HER-2)-enriched, luminal A, luminal B and basal-like/triple negative (TNBC) breast cancer, based on histological and molecular features. At present, clinical decision-making in breast cancer is focused only on the assessment of tumor cells; nevertheless, it has been recognized that the tumor microenvironment (TME) plays a critical biologic role in breast cancer. This is constituted by a large group of immune and non-immune cells, but also by non-cellular components, such as several cytokines. TME is deeply involved in angiogenesis, immune-evasion strategies, and propensity for early metastatic spread, impacting on prognosis and prediction of response to specific treatments. In this review, we focused our attention on the early morphological changes of tumor microenvironment (tumor vasculature features, presence of immune and non-immune cells infiltrating the stroma, levels of cytokines) during breast cancer development. At the same time, we correlate these characteristics with early metastatic propensity (defined as synchronous metastasis or early recurrence) with particular attention to breast cancer subtypes.

Keywords: breast cancer; cytokines; metastasis; tumor angiogenesis; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Different forms of tumor neovascularization. The figure shows the angiogenic-dependent and -independent pathways, through which tumors may provide their blood supply. The two angiogenic-dependent pathways are: (1) sprouting angiogenesis: a dynamic paracrine crosstalk between tumor cells and tumor microenvironment that generates a vascular sprout arising from a pre-existing vessel; (2) intussusceptive angiogenesis: an alternative angiogenic process that consists of the invagination of the capillary walls into the vascular lumen of a pre-existing vessel. The two angiogenic-independent pathways are: (1) vascular mimicry: some tumor cells may generate channels that mimic the function of vessels. These tumor cells have a high plasticity that allows them to acquire endothelial cell-like traits; (2) vessel co-option: tumor cells, migrating along the preexisting vessels of the host organ, hijack the surrounding normal vessels with preservation of the organ pre-existing architecture.
Figure 2
Figure 2
Crosstalk between endothelial cells and pericytes during sprouting angiogenesis: The formation of newly endothelial tubules from pre-existent vessels begins with aberrations in endocytes (ECs)-pericytes (PCs) signaling networks, which induce PCs-ECs dissociation and degradation of basement membrane by mean of proteolytic activities to allow cell migration and for creating space in the matrix. New vessel maturation is characterized by pericyte recruitment, functional pericyte investment of the endothelium, and assembly of ECM components. In this context, PC release pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), acid and basic fibroblast growth factor (βFGF and βFGF), transforming growth factor-β1 (TGFβ1), hypoxia-inducible factors (HIF-1 and HIF-2) and mast cell-derived metalloproteinases (MMP), leading to degradation of the basement membrane, vasodilatation, increased vessel permeability and endothelial tube formation. The recruitment of pericytes, surrounding immature sprouting vessels with consequently pericyte coverage, is mediated principally by the release of TGFβ and platelet-derived growth factor β (PDGFβ) by ECs, which activates the corresponding receptor on pericytes. Conversely to ECs, tumor cell derived PDGFβ may induce the promotion of the pericyte to fibroblast activated cells (CAF) transition, inducing tumor invasion and metastasis through paracrine TGFβ signaling and mechanical pressure. It has also been showed that the angiopoietin (Ang1 and Ang2) signaling pathway may be crucial in the PCs-ECs crosstalk. Ang1 is secreted by periendothelial cells (pericytes, fibroblasts, smooth muscle cells, macrophages) and induces vessel stabilization and pericyte coverage, while Ang2 is principally secreted by activated ECs and promotes pericytes detachment inducing ECs, sprouting and tumor cell intravasation.
Figure 3
Figure 3
Schematic drawing of the role of cellular and non-cellular components in breast stroma during tumor initiation and progression. Within the tumor microenvironment (TME) there is an array of resident cells, non-resident cells, and secretory elements contributing to the progression and metastasis of breast cancer cells. Tumor-infiltrating lymphocytes (TILs) strongly correlate with good prognosis, in particular in triple-negative and HER2-positive breast cancer patients. T-lymphocytes (CD3+) are the main component of TILs and include CD4+, CD8+ and T-regulatory cells (Treg). Effectively, TILs CD8+ and Th1 cytokines correlate with favorable prognosis, whereas it has been reported a strong association between an increase in Treg-infiltrating and –circulating cells and subsequent breast cancer metastases. Tumor-associated macrophages (TAMs) can express a broad spectrum of activation states. They can have a “classical” tumoricidal phenotype (M1) and an “alternatively” activated tumor-promoting phenotype (M2). It is recognized that perivascular macrophages, involved in the tumor microenvironment of metastasis (TMEM), are a subpopulation of TAMs (Tie2+/VEGF+) with strong pro-angiogenic activity. Similar to macrophages in TME, neutrophils can polarize in two distinct subtypes and N2 tumor-associated neutrophils (TANs) inactivate T-lymphocytes and promote cancer growth. Cancer-associated fibroblasts (CAFs) are the main cell component of breast cancer stroma and are able to secrete a wide range of proteases, inflammatory molecules and growth factors, overall inducing tumor progression and worsening clinical outcome. Cancer-associated adipocytes (CAAs) differ from the normal adipocytes in metabolic activity and leptin production and have been shown to be deeply involved in tumor progression and metastasis.
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