Tumor Microenvironment: A Determinant of Dormancy and Metastatic Growth

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Ifeoluwa Oyelade

One of the most impactful breakthroughs in cancer research would be to completely eradicate all cancer cells in the body upon treatment, thereby preventing possible cases of cancer relapse. However, the ability of tumor cells to move out of their primary sites to reside in different organs in the body continues to plague cancer therapy. The tumor cells that have migrated out of their primary tissue or organs to new tissues or organs in the body are called disseminated tumor cells (DTCs). These DTCs, upon arrival at the distant sites, could die as a result of unfavorable conditions, survive in a permissive environment and form metastatic disease or remain in a dormant state (Figure 1).

Fig 1: Fate of Disseminated Tumor Cells (DTCs) in the tumor microenvironment

In a restrictive environment, DTCs outside their primary organs undergo apoptosis; in a permissive environment, DTCs survive and thrive outside their primary organs to formant metastatic lesions and in other cases, DTCs remain in a non-proliferative dormant state only to be reawakened in the presence of certain factors that support or induce activation of dormant cells.

In the dormant state, DTCs can remain non-proliferative for a prolonged time, with the ability to evade cancer therapy techniques. Furthermore, these dormant DTCs could become reactivated in a permissive environment and under appropriate conditions, resulting in a metastatic relapse.

The Tumor microenvironment (TME), which emerges in the course of tumor progression, is the immediate surrounding/environment of cancer cells. The TME comprises blood vessels, immune cells, fibroblasts, adipocytes, signaling molecules, and extracellular matrix. These components have been found to play a role in tumor growth, tumor invasion, metastasis, chemoresistance, and the ability to evade the immune response. The tumor progression ability of the TME is largely influenced by the interactions of cancer cells with the TME and this interaction ultimately determines whether a primary tumor would become eradicated, metastasized, or become dormant. This process can be further explained by the “seed and soil” theory proposed by Steven Paget, which suggests that the “seed” (tumor cell) needs a fertile “soil” (microenvironment) to thrive.

Also, some components of the TME are found to play a role in the regulation of dormant DTCs. They have the ability to either retain the dormant nature of these cells or reactivate dormant DTCs. For example, in mouse models, the presence of type III collagen was found to interrupt the proliferation of tumor cells and force DTCs into a state of dormancy. Also, TGF-2β and bone morphogenetic protein 7 (BMP7), were found to induce dormancy of DTCs. In contrast, the presence of vascular cell adhesion protein 1(VCAM1) induced the reactivation of dormant cells in the bone marrow. Also, the tumor microenvironment enriched with type 1 collagen was found to trigger the exit of tumor cells from dormancy, thereby reactivating them into proliferative and metastatic cells.

The components of the TME are fast becoming an area of focus in cancer research as it plays a vital role in the survival or destruction of cancer cells outside their primary site. In other words, it is a huge determinant of the disease-free survival of cancer patients. As our knowledge of the TME continues to expand, and we begin to have a clearer understanding of the roles of TME in induction or escape from dormancy to form metastatic lesions, it might be time to intensify efforts in determining which of the components of the TME is responsible for the formation of often deadly metastatic disease. This could shed more light on the science of metastasis and manipulating these TME components could present a possible therapeutic target.

Edited by Bhavuk Garg

Referenced Works

Linde, N., Fluegen, G. and Aguirre-Ghiso, J.A (2016). Relationship between Dormant Cancer Cells and their Microenvironment. Adv Cancer Res 132:45-71

Liu, Q., Zhang, H., Jiang, X. et al., (2017) Factors involved in cancer metastasis: a better understanding to “seed and soil” hypothesis. Molecular Cancer 16:176.

Sistigu, A., Musella, M., Galassi, C. et al. (2020) Tuning Cancer Fate: Tumor Microenvironment’s Role in Cancer Stem Cell Quiescence and Reawakening. Frontiers in Immunology 11:2166

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