The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs

Abstract

The fact that certain tumors exhibit a predilection for metastasis to specific organs has been recognized for well over a century now. An extensive body of clinical data and experimental research has confirmed Stephen Paget's original "seed and soil" hypothesis that proposed the organ-preference patterns of tumor metastasis are the product of favorable interactions between metastatic tumor cells (the "seed") and their organ microenvironment (the "soil"). Indeed, many of the first-line therapeutic regimens, currently in use for the treatment of human cancer are designed to target cancer cells (such as chemotherapy) and also to modulate the tumor microenvironment (such as antiangiogenic therapy). While some types of tumors are capable of forming metastases in virtually every organ in the body, the most frequent target organs of metastasis are bone, brain, liver and the lung. In this review, we discuss how tumor-stromal interactions influence metastasis in each of these organs.

Figure 1

Expression of phosphorylated PDGFR-β in clinical bone marrow samples that were collected from patients with prostate cancer. Tumor foci were identified by positive staining for cytokeratin 18 (upper left panel). Additional specimens were labeled with an antibody specific for the phosphorylated form of the PDGFR-β (remaining panels).

Figure 2

Colon cancer cells produce TGFα that acts in an autocrine manner to promote tumor growth and in a paracrine fashion to activate angiogenic programs in resident endothelial cells (1). This signaling is mediated by the EGFR that is expressed on both cell populations. Tumor cells express VEGFA that reinforces the angiogenic response (2), and the expansion in the tumor vascular surface area increases the likelihood of haematogenous metastasis. VEGFA is also a potent chemoattractant for macrophages (3), which secrete VEGFC in the tumor microenvironment (4). VEGFC binds to VEGFR-3 expressed on lymphatic endothelial cells and stimulates lymphangiogenesis (5), which facilitates the spread of tumor cells to regional lymph nodes. TGFα produced by colon tumor cells binds to the myofibroblast EGFR, which respond by entering the cell cycle and increasing their production of MMP (6). MMP degradation of the extracellular matrix enhances tumor cell invasion.

Figure 3

Tumor cell-astrocyte interaction in experimental 3LL brain metastases. Brain tissues were sectioned and incubated with an antibody directed against GFAP, which labels reactive astrocytes. Reactive astrocytes (brown) encircle and infiltrate the tumor mass (blue). No GFAP-positive astrocytes were detected in the same location of the brain in non-tumor-bearing mice (data not shown).