Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis

Abstract

Metastasis is the consequence of a cancer cell that disperses from the primary tumor, travels throughout the body, and invades and colonizes a distant site. On the basis of Paget's 1889 hypothesis, the majority of modern metastasis research focuses on the properties of the metastatic "seed and soil," but the implications of the primary tumor "soil" have been largely neglected. The rare lethal metastatic "seed" arises as a result of the selective pressures in the primary tumor. Optimal foraging theory describes how cancer cells adopt a mobile foraging strategy to balance predation risk and resource reward. Further selection in the dispersal corridors leading out of the primary tumor enhances the adaptive profile of the potentially metastatic cell. This review focuses on the selective pressures of the primary tumor "soil" that generate lethal metastatic "seeds" which is essential to understanding this critical component of prostate cancer metastasis.Implication: Elucidating the selective pressures of the primary tumor "soil" that generate lethal metastatic "seeds" is essential to understand how and why metastasis occurs in prostate cancer. Mol Cancer Res; 15(4); 361-70. ©2017 AACR.

Figure 1. Steps of the metastatic process

Metastasis is characterized by a series of sequential steps: primary tumor formation, recruitment of blood vessels through angiogenesis, cancer cell invasion of local tissue, and entry into dispersal corridors such as blood vessels. Disseminated cells travel through the circulation and upon reaching a suitable secondary site such as the bone, extravasate from the blood vessels and colonize to form bone metastases. (Modified from Servier Medical Art by Servier licensed under CC BY 3.0.)

Figure 2. Optimal foraging of prostate cancer cells

The optimal foraging strategy employed by a cancer cell is influenced by three interacting factors: available resources (e.g. oxygen, glucose), predation risk (e.g. cytotoxic T cells, M1 macrophages), and movement ability (e.g. mesenchymal phenotype, permissible ECM).

Figure 3. Prostate cancer resource patches and dispersal corridors

(A) Primary prostate tumor from prostate cancer patient radical prostatectomy. (a: lymphovascular vessel, b: nerve, c: intraductal carcinoma, d: stromal infiltration) (B) Prostate cancer resource patches: Colored regions represent patches within the primary tumor and depict spatial heterogeneity at single moment in time. Variations in color represent variations in patch characteristics (i.e. resource and predation risk). Importantly, though not depicted, patch geography and characteristics change over time. (C) Dispersal corridors including blood vessels (red and maroon), lymph vessels (green), and nerves (orange) intersect primary tumor patches and provide a route for long-distance dissemination out of the primary tumor habitat. (H&E; scale bar = 300 μm; image courtesy of Dr. Tamara Lotan, Johns Hopkins University)

Figure 4. Path of dispersing prostate cancer cells from the primary tumor

Prostate cancer cells disseminate from the primary tumor via venous blood vessels (blue), lymph vessels (green), or nerves (orange). Nerve-disseminated cells enter the lymph and all cancer cells in the lymph pass through at least one lymph node before entering the venous blood supply. CTCs are then carried through the body via the blood circulation. CTCs pass through the through the heart and lungs to enter the arterial blood supply. CTCs are carried with the blood through the arterial system, entering distant organ capillary beds at random. Upon reaching a suitable secondary site, such as the bone, cells must extravasate from the blood vessel to colonize the metastatic site. Image printed here with permission from the source: Tim Phelps (C)JHU/AAAM 2016, Department of Art as Applied to Medicine, The Johns Hopkins University School of Medicine.

Figure 5. Inefficiency of prostate cancer metastasis

Of the cells that disseminate from the primary tumor (detected as CTCs from the venous circulation), very few become bone DTCs and even fewer eventually form clinical metastases. The inefficiency of each of step compounds with progression along the metastatic process.