An overview of the tumor microenvironment, from cells to complex networks (Review)

Abstract

For a long period, cancer has been believed to be a gene disease, in which oncogenic and suppressor mutations accumulate gradually, finally leading to the malignant transformation of cells. This vision has changed in the last few years, the involvement of the tumor microenvironment, the non-malignant part of the tumors, as an important contributor to the malignant growth being now largely recognized. There is a consensus according to which the understanding of the tumor microenvironment is important as a means to develop new approaches in the therapy of cancer. In this context, the present study is a review of the different types of non-malignant cells that can be found in tumors, with their pro or antitumoral actions, presence in tumors and therapeutic targeting. These cells establish complex relations between them, through cytokines, exosomes, cell adhesion, co-stimulation and co-inhibition; these relations will also be examined in the present work.

Keywords: biogenesis; immunity; microenvironment; network.

Figure 1

Biogenesis of the tumor microenvironment. The development of the tumor leads to angiogenesis and to recruitment of different cells in the tumor; immunosuppression appears also as a consequence of the tumoral growth. The tumoral fibroblasts secrete a dysregulated extracellular matrix which contributes to the immune suppression. Complex relations are established between the resulting microenvironment components.

Figure 2

Immune response in malignant tumors. The presence of the danger signals within the tumor triggers an innate immune response; the antigen presentation by the APCs (antigen-presenting cells) leads to the activation of the CD8⁺ and CD4⁺ lymphocytes; low level of MHC proteins or increased atypical MHC such as MICA activate NK lymphocytes, while particular subsets such as γδ or NKT-cells respond to antigens like phospho-antigens or CD1d-presented lipidic antigens. A multimodal immune response develops, adequate to the signals that the tumor presents. The different segments of the immune system cooperate for an optimal response.

Figure 3

Relations between the tumor and the immune response. The immune response and tumors interact in multiple ways. The immunosuppression from the tumor microenvironment inhibits the antigen-specific lymphocytes, while innate immune cells are influenced by tumor-derived factors, cytokines and exosomes to aquire a protumoral profile. The dysregulated extracellular matrix contributes to the suppression, increasing also the survival and the invasiveness of the tumor cells; chronic inflammation that develops supports the tumoral growth, while certain profiles of adaptive response such as Th2 or Th17 are also mainly protumoral.

Figure 4

Immunotherapy adresses tumors by inhibiting angiogenesis, tumor-associated cells and immunosuppression, and also by stimulating different cells with tumoricidal potential, through antibodies (monoclonal or bispecific), adoptive therapies, vaccines, TLR stimulation or interleukins. A network view of the different immunotherapies is shown.