Metastasis as a systemic disease: molecular insights and clinical implications

Abstract

Metastasis is a complex systemic disease that develops as a result of interactions between tumor cells and their local and distant microenvironments. Local and systemic immune-related changes play especially critical roles in limiting or enabling the development of metastatic disease. Although anti-tumor immune responses likely eliminate most early primary and metastatic lesions, factors secreted by cancer or stromal cells in the primary tumor can mobilize and activate cells in distant organs in a way that promotes the outgrowth of disseminated cancer cells into macrometastatic lesions. Therefore, the prevention, detection, and effective treatment of metastatic disease require a deeper understanding of the systemic effects of primary tumors as well as predisposing hereditary and acquired host factors including chronic inflammatory conditions. The success of immunotherapy in a subset of cancer patients is an example of how modulating the microenvironment and tumor-immune cell interactions can be exploited for the effective eradiation of even advanced-stage tumors. Here, we highlight emerging insights and clinical implications of cancer as a systemic disease.

Keywords: Host factors; Metastasis; Systemic effects.

Figure 1.. Mechanism of metastatic progression.

During primary tumor growth cancer cells can shed into the circulation and disseminate to distant sites, which may even occur at a very early stage of primary tumor development. Tumor-secreted factors can recruit, expand and activate various stromal cells, including spleen- and bone marrow-resident cells, and facilitate the formation of pre-metastatic niches at secondary sites. The recruited stromal cells aid the dissemination of carcinoma cells survival in circulation, and metastatic seeding and colonization. Immune evasion and angiogenesis are necessary steps of tumor progression mediated by tumor- and stroma-derived factors. Self-seeding of the tumor at later stages and re-seeding from metastatic lesions increase intratumoral heterogeneity and the risk of therapeutic resistance.

Figure 2.. Clonality of métastasés.

Metastatic lesions can be monoclonal or polyclonal. Monoclonal seeding of circulating tumor cells (CTCs) shed from the primary tumor or monoclonal expansion of a subclone within a polyclonal metastasis can give rise to a monoclonal metastatic lesion. Polyclonal métastasés can emerge through multiple different mechanisms. Clonal cooperation promotes the metastatic abilities of poorly metastatic subclones. Collective migration and dissemination as CTC clusters lead to formation of polyclonal disseminated tumor cell (DTC) clusters at the secondary site. Re-seeding from the primary tumor or from other metastatic lesions can also contribute to metastatic heterogeneity.

Figure 2.. Clonality of métastasés.

Metastatic lesions can be monoclonal or polyclonal. Monoclonal seeding of circulating tumor cells (CTCs) shed from the primary tumor or monoclonal expansion of a subclone within a polyclonal metastasis can give rise to a monoclonal metastatic lesion. Polyclonal métastasés can emerge through multiple different mechanisms. Clonal cooperation promotes the metastatic abilities of poorly metastatic subclones. Collective migration and dissemination as CTC clusters lead to formation of polyclonal disseminated tumor cell (DTC) clusters at the secondary site. Re-seeding from the primary tumor or from other metastatic lesions can also contribute to metastatic heterogeneity.

Figure 3.. Local and systemic factors contributing to metastatic progression.

Primary tumors secrete various factors that act systemically to promote metastatic dissemination (blue box). These factors can affect stromal cells at distant sites (systemic macroenvironments), such as the spleen, liver and bone marrow, leading to their activation, expansion, and/or recruitment. Several cancer-related complications arise due to expansion of stromal cells, such as neutrophilia (increased neutrophil numbers) and thrombocytosis (increased platelet numbers). Activated and recruited stromal cells in turn can affect metastasis at the primary site (not shown), in circulation or at distant tissues (local microenvironments). Interactions of cancer cells and stromal cells at distant sites are tissue-specific as each secondary site varies in its physical properties and cellular and matrix composition. For instance, fenestrated endothelia in the bone and lung are likely permissive to tumor cell passage, while lung capillaries lined with a basement membrane and the blood-brain-barrier require specific mediators of cancer cell extravasation for successful metastatic seeding. Anti-tumor immune cells, such as cytotoxic CD8⁺ T cells which are expanded and recruited from the lymph node, can clear tumor cells from the circulation or at distant sites. Tumor cells gain immune protection through coating by platelets and actions of other immune and stromal cells, including neutrophils. The latter can also form neutrophil extracellular traps (NETs) to promote extravasation.