Tumor microenvironment

The Tumor Microenvironment: A Malignancy Bunker

The tumor microenvironment (TME) or tumor niche is a highly heterogeneous complex that is comprised of cells such as stromal cells, immune cells, epithelial cells, and a network of extracellular macromolecules.

This complex provides support for cancer cells within the extracellular matrix (EC) and plays a key role in promoting their progression into a more malignant phenotype [1]. This support is provided through intercellular communications that are mediated by secreted growth factors and cytokines to promote tumorigenesis, angiogenesis, invasion, and metastasis. 

A collaborative Malignant Effort

Each cell within the TME has specific and complementary roles to play. Immune cells that are supposed to attack and eliminate cancer cells, promote the chronic inflammatory status of the TME which enhances tumor proliferation, invasion, and metastasis.

For instance, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) secrete transforming growth factor-beta (TGF-β), which contributes to cancer invasion and metastasis [2].

Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into various cell types such as osteocytes, adipocytes, and chondrocytes. These cells also secrete TGF-β and contribute to invasion and metastasis. Other cells such as cancer-associated fibroblasts (CAFs) provide a mechanical supportive role via enhanced production of fibrillar collagen.

They also secrete the cytokine CXCL12 (C-X-C motif chemokine ligand 12) and growth factors such as the hepatocyte growth factor (HGF), the vascular endothelial growth factor (VEGF), and the platelet-derived growth factor (PDGF), which significantly contribute to cancer proliferation, invasion, and metastasis.

Finally, endothelial cells (ECs) that are one of the building blocks of vessels, are stimulated by angiogenic factors such as the vascular endothelial growth factor (VEGF) resulting in increased tumor vasculature (angiogenesis) and enhanced tumor growth and metastasis.

The TME and Resistance to Cancer Therapies

Drug resistance in cancer is associated with mechanisms that limit the number of drugs reaching the tumor and those affecting the tumor microenvironment [3]. The latter mechanism has shown that damaged or irradiated fibroblasts could support tumor cell growth and suggested that fibroblasts could potentially respond and affect cancer therapy [4].

The tumor vasculature has also been suggested to act as a barrier to optimal drug delivery [5]. Immune cells promote the chronic inflammatory status of the TME which renders it refractory to anti-VEGF therapy by secreting factors that compensate for VEGF loss to support angiogenesis [6].


The TME is a highly heterogeneous complex that enhances tumor proliferation, invasion, and metastasis. This complexity resides in its composition which involves several cellular players that orchestrate the maintenance and perpetuation of malignant phenotypes and contribute to drug resistance. Therefore, therapies require higher levels of complexity to target each component of the TME.


[1] Whiteside, T.L., 2008. The tumor microenvironment and its role in promoting tumor growth. Oncogene27(45), pp.5904-5912.

[2] Barbato, L., Bocchetti, M., Di Biase, A. and Regad, T., 2019. Cancer stem cells and targeting strategies. Cells8(8), p.926.

[3] Junttila, M.R. and De Sauvage, F.J., 2013. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature501(7467), pp.346-354.

[4] Ohuchida, K., Mizumoto, K., Murakami, M., Qian, L.W., Sato, N., Nagai, E., Matsumoto, K., Nakamura, T. and Tanaka, M., 2004. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer research64(9), pp.3215-3222.

[5] Jain, R.K., 2005. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science307(5706), pp.58-62.

[6] Shojaei, F., Wu, X., Malik, A.K., Zhong, C., Baldwin, M.E., Schanz, S., Fuh, G., Gerber, H.P. and Ferrara, N., 2007. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+ Gr1+ myeloid cells. Nature biotechnology25(8), pp.911-920.

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