Seed and soil: A conceptual framework of metastasis for clinicians

Abstract

Most mortality from cancer is secondary to metastasis. Metastasis refers both to the process by which tumor cells establish themselves at organs distinct from where they originated and to the life-threatening lesions themselves. Metastases are often resistant to conventional therapies, highlighting a key distinction between these progeny lesions and the primary tumor from which they arose. Here, we summarize recent advances in understanding and targeting primary tumors and the mechanisms and therapeutic challenges of metastasis.

Figure 1. Steps of the Invasion-Metastasis Cascade

Normal epithelium is depicted in yellow, tumor cells in red with jagged edges. (A) Normal epithelium with lumen (B) Carcinoma in situ: neoplastic transformation occurs with tumor cells confined within the epithelial basement membrane (C) Invasion: tumor cells fill epithelial lumen and begin to invade beyond the basement membrane and into the interstitial space (D) Neovascularization: vasculature is recruited to perfuse the expanding tumor (E) Intravasation: tumor cells invade into the vasculature and gain access to the systemic circulation; tumor cells travel to remote sites via circulation (F) Extravasation and metastatic seeding: tumor cells exit the vasculature and arrive at distant organ sites (G) Metastatic colonization: an extreme minority of seeded tumor cells adapt to the foreign environment of the distant site and begin to proliferate to form a clinically detectable metastatic lesion.

Figure 2. Models of Metastatic Progression

Normal epithelium is depicted in yellow, tumor cells in red with jagged edges. (A) The clonal selection model: as the tumor progresses, tumor cells acquire mutations, some of which enhance metastatic capacity and only those tumor cells with favorable mutations (purple) metastasize. Genotypically distinct tumor cells are depicted in different colors. (B) The cancer stem cell model: the tumor is made of a minor subpopulation of cancer stem cells (green) that are the only cells within the tumor that can initiate new tumors, including metastases.