Tumor microenvironment complexity and therapeutic implications at a glance

Abstract

The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices. Video abstract.

Keywords: Apoptotic bodies; Cancer cell interactions; Cancer models; Cancer therapy; Cell-free DNA; Circulating tumor cells; Exosome; Extracellular matrix; Horizontal transfer; Stroma cell; Tumor microenvironment.

Fig. 1

Tumor microenvironment at a glance. Tumor cells hijack different cellular and non-cellular non-malignant components of TME to promote their own growth and survival under hostile conditions. Meanwhile, the mediators for such contacts can be soluble factors (chemokines/cytokines/growth factors, etc.), or those that enable horizontal genetic/biomaterial transfer including cfDNA, apoptotic bodies, CTCs, and exosomes

Fig. 2

Exploiting different cellular and non-cellular components of TME for effective cancer targeting

Fig. 3

Design and working principle of aptamer-dendrimer (G4.5) nanomaterial for dual targeting of CTCs to reduce cancer metastatic burden. A, schematics of ring aptamers cCAP1 for targeting EpCAM and cCAP2 for targeting Her2 on CTCs. B, C, construction of aptamer ring conjugate (cCAP1-G4.5-cCAP2) for simultaneous binding and capturing of two CTC markers. D, Ex vivo analysis of CTCs in the blood of breast cancer patients captured by cCAP1-G4.5-cCAP2. Adapted with permission from [154]. Copyright (2017), American Chemical Society

Fig. 4

CTCs as valuable diagnostics for cancer management. DNA hydrogel-based liquid biopsy provides a highly sensitive platform for isolating CTCs expressing EpCAM and enables further live analysis with minimal damage. Adapted with permission from [156]. Copyright (2017) American Chemical Society

Fig. 5

A schematic representation of the exosome preparation. a-b, Exosomes derived either from the human lung cancer cell line A549 (A-Exo) with high EGFR expression or from the human lung fibroblast cell line HELF (H-Exo) with low EGFR expression. The isolated exosomes were further transfected with a DNA sequence coding for CD9 and CD63 markers. Synthesis and functionalization of MSN with EGFR-targeting aptamers. c, A-Exo is recognized and captured by MSN-AP in cell media and rat blood. d, MSN-AP eliminates circulating exosomes in animals and patient blood. Adapted from Springer Nature: Nature Communication, Copyright (2019) [188]