Proteoglycans and Immunobiology of Cancer-Therapeutic Implications

Abstract

Disparity during the resolution of inflammation is closely related with the initiation and progression of the tumorigenesis. The transformed cells, through continuously evolving interactions, participate in various exchanges with the surrounding microenvironment consisting of extracellular matrix (ECM) components, cytokines embedded in the ECM, as well as the stromal cells. Proteoglycans (PGs), complex molecules consisting of a protein core into which one or more glycosaminoglycan (GAG) chains are covalently tethered, are important regulators of the cell/matrix interface and, consecutively, biological functions. The discrete expression of PGs and their interacting partners has been distinguished as specific for disease development in diverse cancer types. In this mini-review, we will critically discuss the roles of PGs in the complex processes of cancer-associated modulation of the immune response and analyze their mechanisms of action. A deeper understanding of mechanisms which are capable of regulating the immune response could be harnessed to treat malignant disease.

Keywords: cancer; extracellular matrix; immunobiology; proteoglycans; remodeling.

Figure 1

Immunobiology of cancer cycle. When un-damaged tissue (A) is subjected to injury, innate immunity cells (neutrophils and macrophages type M1) infiltrate the tissue and generate an acute inflammation (B) that triggers the repair cascade guiding the tissue to its un-damaged status. ECM is altered and contributes to inflammatory processes. If the inflammation is sustained and has chronic characteristics (C), in addition to M1 macrophages the tissue is infiltrated with adaptive immunity cells (Th1, Tc, Th17); the pre-cancerous lesion (D) can return to its normal un-damaged status. At these stages the elimination of tumor development is possible. If the chronic inflammation persists (E) then the pre-cancerous lesion evolves into a primary tumor. The primary tumor can be infiltrated by M1, Th1, Tc, Th17 cells (F) with intense anti-tumoral activity which can restrain the tumorigenesis process and establish the immune equilibrium stage. In contrast, when the infiltrating cells are M2 type macrophages Th2, Treg lymphocytes (G) a pro-tumorigenesis milieu is enhanced and the primary tumor evolves into an aggressive/metastatic tumor. The ECM is modulated by tumor/stromal -cells and gains new immunosuppressive characteristics that favor metastasis (H). This last stage of the tumor-immune cycle is characterized by the escape of tumor cells from the immune control.

Figure 2

Immunomodulatory roles of biglycan. (A) By binding to TLR2 or 4 on macrophages' biglycan induces cytokine (TNF-α, CCL2 or IL-1β) release; (B) Crosstalk between TLR2/4- and P2X induces NLRP3 inflamozone and IL-1β activation and consequent neutrophil recruitment; (C) Soluble biglycan initiates Toll/interleukin (IL)-1R domain-containing adaptor activation inducing interferon (IFN)-β (TRIF) activities for T-lymphocyte recruitment; (D) Biglycans' binding determines CD14/TLR2/TLR4 complex formation and discrete downstream signaling; (E) Biglycan binding to specific TLR receptors discriminately activates NADPH oxidase (NOX) 1, 2, and 4 enzymes and regulates their downstream ROS production resulting in both positive or negative modulation of IL-1β synthesis; or in the stimulation of macrophages and dendritic cells to express chemokine (C-X-C) ligand 13 (CXCL13), the major chemoattractant for B and B1 lymphocytes.