Cellular Interactions in the Tumor Microenvironment: The Role of Secretome

Abstract

Over the past years, it has become evident that cancer initiation and progression depends on several components of the tumor microenvironment, including inflammatory and immune cells, fibroblasts, endothelial cells, adipocytes, and extracellular matrix. These components of the tumor microenvironment and the neoplastic cells interact with each other providing pro and antitumor signals. The tumor-stroma communication occurs directly between cells or via a variety of molecules secreted, such as growth factors, cytokines, chemokines and microRNAs. This secretome, which derives not only from tumor cells but also from cancer-associated stromal cells, is an important source of key regulators of the tumorigenic process. Their screening and characterization could provide useful biomarkers to improve cancer diagnosis, prognosis, and monitoring of treatment responses.

Keywords: Cancer; Microenvironment; Secretome..

Figure 1

The crosstalk between neoplastic cells and cancer-associated fibroblasts (CAFs). Neoplastic cells induce stationary CAFs to synthesize cytokines, matrix metalloproteinases (MMPs), and growth factors (GFs), such as TGF-beta, leading to proliferation, migration, invasion and metastasis. Motile CAFs can be derived from neoplastic cells that have undergone epithelial-mesenchymal transition (EMT) by TGF-beta induction. CAFs may exhibit tumor suppressive activities inducing apoptosis and preventing proliferation.

Figure 2

Senescence-associated secretome. Senescence-associated microenvironment is rich in matrix metalloproteinases (MMPs), cytokines, growth and angiogenic factors. Senescent cells may secrete pro-senescent, pro-apoptotic and anti-angiogenic factors, as well signals to induce immune cells to modulate tissue regeneration and senescent cell removal.

Figure 3

Cancer secretome, inflammation and angiogenesis. Gene mutations induce the expression of inflammation-related programs in neoplastic cells with activation of several transcription factors. The resulting signaling events induce immune cells to produce inflammatory mediators, including cytokines, chemokines, cyclooxygenase-2 (COX-2) and prostaglandins, which will trigger a cascade of signals in inflammatory, stromal and tumor cells. Neutrophils can release matrix metalloproteinases (MMPs), nitric oxide (NO₂), reactive oxygen species (ROS) and elastase, promoting cell proliferation and epithelial-mesenchymal transition (EMT). Neoplastic and immune cells can also secrete pro-angiogenic factors, including growth factors (VEGF, FGF, PDGF, EGF, HDGF), interleukins, cytokines and chemokines (IL-8, IL-18) and cysteine-rich angiogenic inducer CYR61.