Table 1.

Examples of tumour microenvironment (TME) heterogeneity and their consequences on cancer development.

TME Cell Types	TME Heterogeneity	Consequences on Tumour Development	References
Cancer-associated fibroblasts (CAFs)	CAFs differ by their origins (cellular precursors and cellular locations) and their marker expression profiles. CAFs subgroups are differentially expressed depending on the cancer types.	CAF subsets display opposite functions in cancers: some favour cancer development through the promotion of angiogenesis, metastasis and drug resistance, while others exhibit tumour-suppressor properties by contributing to growth inhibition, immune surveillance of the tumour and drug sensitivity.	[52]
Immune cells (macrophages, dendritic cells, mast cells, natural killer cells, B and T lymphocytes)	Variable levels of immune infiltration are observed in tumours depending on cancer types and subtypes. The immune cell composition (innate/adaptive immune cells, immune cell types) also differs between tumours.	Numerous studies report the interest of tumour-infiltrating lymphocytes (TILs) as a major prognostic marker in diverse cancers. High density of CD8+ T cells in tumours is strongly correlated with good prognosis, while high regulatory T-cell (Tregs) infiltration was associated with early recurrence and poor outcomes. In the same way, high density of NK cells in tumours was shown to predict good patient survival. Tumour-associated macrophages and neutrophils promote tumour cell plasticity and cancer stem cell phenotype, notably though the secretion of specific cytokines.	[53,54,55]
Tumour endothelial cells (TECs)	TECs show differences in terms of origins, morphology, structure, functions and marker expression. TECs derived from highly metastatic tumours harbour more cytogenic abnormalities and proangiogenic properties than those from tumours with low metastasis. TECs from tumours with high metastatic potential display a stem cell-like phenotype with the remarkable capacity to form spheres.	The overexpression of adhesion molecules in TECs allows cancer cell extravasation and metastasis spreading. TECs can secrete angiocrine factors at various levels that contribute to cancer cell proliferation, migration, invasion and angiogenesis. TECs also contribute to the emergence of drug resistance by increasing the expression of ATP-binding cassette transporters or helping tumour cells to switch to resistant phenotypes. TECs also modulate cancer immune surveillance by secreting growth factors that inhibit immune cells homing and induce the apoptosis of activated CD8+ T cells. TECs expressing PD-L1 marker hamper T cell activation.	[56,57,58]
Extracellular matrix (ECM): collagens, proteoglycans, fibronectin, elastins, laminins, hyaluronans	Proportion of ECM in tumours, ECM composition, architecture and posttranslational modifications are highly variable from a tumour to another.	Increased amounts of collagens in ECM of pancreatic cancers is associated with poor prognosis and chemoresistance. The expression levels of certain collagen isoforms (notably increased Col I levels and decreased Col IV levels) are correlated with stage of cancers and poor prognosis. Enhanced laminin expression and its anarchic distribution as well as high hyaluronic acid levels are correlated with poor clinical outcomes. Abundant and rigid ECM in tumours can act as a barrier and protect tumour cells from therapeutic agents. The stiffness of ECM and its enrichment in hyaluronic acid and Col I isoform drive epithelial-to-mesenchymal transition and promote metastasis and drug resistance.	[59]
Cancer-associated adipocytes (CAAs)	Less is known about the heterogeneity in the adipocyte part of the ECM. CAAs are characterised by irregular morphologies with decreased lipid content and reduced differentiation marker expression compared to normal mature adipocytes.	Growing evidence highlight the role of CAAs in the development of certain tumour types. CAAs interact with cancers cells and induce the reprogramming of their energy metabolism, the development of chemoresistance and the secretion of adipokines that modify the behaviour of tumour cells.	[60]