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Review
. 2020 Jan 3;18(1):1.
doi: 10.1186/s12967-019-02189-8.

Tumor microenvironment differences between primary tumor and brain metastases

Bernardo Cacho-Díaz  1 , Donovan R García-Botello  2 , Talia Wegman-Ostrosky  3 , Gervith Reyes-Soto  2 , Elizabeth Ortiz-Sánchez  3 , Luis Alonso Herrera-Montalvo  4
Affiliations
Review

Tumor microenvironment differences between primary tumor and brain metastases

Bernardo Cacho-Díaz et al. J Transl Med. .

Abstract

The present review aimed to discuss contemporary scientific literature involving differences between the tumor microenvironment (TME) in melanoma, lung cancer, and breast cancer in their primary site and TME in brain metastases (BM). TME plays a fundamental role in the behavior of cancer. In the process of carcinogenesis, cells such as fibroblasts, macrophages, endothelial cells, natural killer cells, and other cells can perpetuate and progress carcinogenesis via the secretion of molecules. Oxygen concentration, growth factors, and receptors in TME initiate angiogenesis and are examples of the importance of microenvironmental conditions in the performance of neoplastic cells. The most frequent malignant brain tumors are metastatic in origin and primarily originate from lung cancer, breast cancer, and melanoma. Metastatic cancer cells have to adhere to and penetrate the blood-brain barrier (BBB). After traversing BBB, these cells have to survive by producing various cytokines, chemokines, and mediators to modify their new TME. The microenvironment of these metastases is currently being studied owing to the discovery of new therapeutic targets. In these three types of tumors, treatment is more effective in the primary tumor than in BM due to several factors, including BBB. Understanding the differences in the characteristics of the microenvironment surrounding the primary tumor and their respective metastasis might help improve strategies to comprehend cancer.

Keywords: Brain metastases; Cancer; Tumor microenvironment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic representation of protein expression, molecular pahtways, facilitators and mutations involved in the genesis of brain metastases from melanoma, breast and lung cancer. Breast cancer cells: Upregulated expression of A.R. (androgen receptor), P.R. (progesterone receptor) and E.R .(estrogen receptor) in the primary tumor. miRNA-509 → Rhoc/TNF pathway → BBB permeability/MMP9 in Circulating tumor cells (CTCs). miRNA-31, -126,-335 suppress metastasic spread. miRNA-7 downregulates KLFM pathway in stem cells. Cathepsin S (CTSS) proteolytic processing of the junction adhesion molecule (JAM). The N-acetylgalactosaminidase α2,6 sialyltransferase 5 (ST6GALNAC5) has been identified as a facilitator of tumor cell/brain endothelial adhesion. The chemokine receptor CXCR4 and its ligand CXCL12 increase vascular permeability and activation of the PI-3K/AKT pathway. Lung Cancer cells: Upregulated EGFR, PI3K, Keap-1, Nfr2, P300, Tp53, Rad54L2, NTRK3, and TARX. miRNA-328 upregulates the PKACA pathway. miRNA-378 is upregulated and miRNA-145 downregulated. IncRNA MALAT1 induces EMT and HOTAIR high expression in BM. The Rho kinase signaling, involved in intracellular junction disruption, has been found activated in this transendothelial migration. Melanoma Cancer cells: Upregulated BRAF mutation, induce PI3K/AKT pathway. miRNA-210 was overexpressed in exosomes of BM cells and miRNA 19a and miRNA-29c were downregulated in exosomes BM cells. In CTC, the membrane-bound melanotransferrin correlates with brain endothelial adhesion
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