Cancer: a mirrored room between tumor bulk and tumor microenvironment

Abstract

It has been well documented that the tumor microenvironment (TME) plays a key role in the promotion of drug resistance, the support of tumor progression, invasiveness, metastasis, and even the maintenance of a cancer stem-like phenotype. Here, we reviewed TME formation presenting it as a reflection of a tumor's own organization during the different stages of tumor development. Interestingly, functionally different groups of stromal cells seem to have specific spatial distributions within the TME that change as the tumor evolves into advanced stage progression which correlates with the fact that cancer stem-like cells (CSCs) are located in the edges of solid tumor masses in advanced tumors.We also focus on the continuos feedback that is established between a tumor and its surroundings. The "talk" between tumor mass cells and TME stromal cells, marks the evolution of both interlocuting cell types. For instance, the metabolic and functional transformations that stromal cells undergo due to tumor corrupting activity.Moreover, the molecular basis of metastatic spread is also approached, making special emphasis on the site-specific pre-metastatic niche formation as another reflection of the primary tumor molecular signature.Finally, several therapeutic approaches targeting primary TME and pre-metastatic niche are suggested. For instance, a systematic analysis of the TME just adjacent to the tumor mass to establish the proportion of myofibroblasts-like cancer-associated fibroblasts (CAFs) which may in turn correspond to stemness and metastases-promotion. Or the implementation of "re-education" therapies consisting of switching tumor-supportive stromal cells into tumor-suppressive ones. In summary, to improve our clinical management of cancer, it is crucial to understand and learn how to manage the close interaction between TME and metastasis.

Keywords: Cancer-associated fibroblasts; Metastasis; Pre-metastatic niche; Tumor microenvironment; Tumor-associated macrophages.

Fig. 1

Sub-microenvironments within the TME of solid malignancies. TME is composed of an extensive vascular network, lymphatic vessels, soluble molecules, extracellular matrix and cells. Molecular factors secreted by cancerous cells, including CSCs, promote the corruption of healthy cells and the nature of the tumoral cells appears to condition the surrounding microenvironment. Based on this, it has been proposed two different sub-microenvironments: (i) a regenerative-like TME with a high accumulation of myofibroblast-like CAFs and tumor-supportive M2 TAMs located close to the CSCs in the tumor mass edges; and (ii) a pro-inflammatory TME with a high accumulation of both pro-inflammatory CAFs and tumor-suppressive M1 TAMs more distant from CSCs localization. Created with BioRender.com

Fig. 2

Hypothetical stages of primary solid tumors. Stage I: The tumor is small and has not spread to distant organs. Stage II: The tumor is larger and a pro-inflammatory TME appeared with a high accumulation of both pro-inflammatory CAFs and M1 TAMs. Stage III: high accumulation of pro-inflammatory CAFs and M1 TAMs, CSCs mainly in the edges of tumor mass start to appear. Stage IV: High appearance of CSCs in the edges of tumor mass, the molecular balance changes and promotes the generation of a regenerative-like microenvironment. This regenerative-like microenvironment prompts the accumulation of both myofibroblast-like CAFs subtype (also termed “TGFβ-responsive CAFs”) and tumor-supportive M2 TAMs polarized by TGFβ signalling. The cancer spreads to distant organs. Created with BioRender.com

Fig. 3

Formation of a pre-metastatic niche. The formation of a pre-metastatic niche (with both CAFs and TAMs) occurs before metastatic growth and it is promoted by primary tumor-derived soluble factors and exosomes. The specific integrins patterns on the exosome surface may condition the specific cellular targets of such exosomes. Therefore, the molecular signature of the pre-metastatic niche and its site-selective location may be considered as a reflection of the primary tumor molecular signature. Created with BioRender.com