The overall pathogenesis of metastatic growth is a subject of concern to all individuals seeking a better understanding of the cause and control of cancer. It is usually the metastatic lesions of a primary neoplasm that are the direct or indirect cause of the demise of the patient with cancer. Since the first realization that metastatic neoplasia originated from a primary neoplasm (Chapter 1), the methods by which metastatic cells successfully colonize distant tissues have been investi- gated. Figure 10.11 is a diagram of the overall pathogenesis of metastatic lesions in a general sense.
Vascularization of a primary neoplasm involves an interesting interaction between neo- plastic cells and the host, the latter supplying the vasculature—a topic discussed in Chapter 18. Invasion into the vascular system occurs by mechanisms that have already been discussed (Fig- ure 10.8 and text). Neoplastic cells within the circulation interact with blood platelets, lympho- cytes, and other circulating blood cells of the host. Fibrinogen and fibrin, its polymeric product, are likely to be related in a second, indirect manner to the formation of metastases (Malone et al., 1979). The interaction of neoplastic cells with platelets during and after their “docking” (Figure 10.10) is also a critical factor in the initial establishment of a metastatic clone. The “locking” or subsequent late phase of the process depicted in Figure 10.10 involves a firmer adhesion mediated by activation-dependent integrins and potential interaction with blood coagu- lation elements, especially blood platelets. Neoplastic cells in vitro exhibit the capability to cause platelet aggregation, which also involves surface carbohydrate-receptor interactions (Honn et al., 1992). The combination of platelet interaction with the neoplastic cell to form a minithrombus and the interaction of integrins with surface molecules on the endothelial cell sta- bilize the interaction of the neoplastic cell with the endothelial surface. Following this, there
Figure 10.11 The pathogenesis of metastasis. Note that the extension from the primary neoplasm in- volves invasion into the vascular system and the subsequent development of metastases through the dock- ing and locking mechanisms in Figure 10.10. (Adapted from Poste and Fidler, 1980, with permission of the authors and publishers.)
occurs both the release of proteases, as in the invasive process (Figure 10.8), as well as endothe- lial cell retraction to aid in the invasive process of the metastatic cell through the endothelial membrane. Furthermore, platelets release a variety of growth factors, including the platelet- derived growth factor (PDGF) and transforming growth factor-β (TGF-β) (Chapter 16), which can enhance growth of the metastatic clone. Subsequent to extravasation or invasion through the blood vessel wall, subsequent growth of the metastatic clone depends on a variety of complex interactions between the neoplastic cell population and that of the host. Paramount among these interactions is the development of blood vessels (angiogenesis) from normal host cells to supply the vasculature, oxygen, and nutrients to the developing neoplasm. This subject is considered more extensively as a complex host-tumor relationship in Chapter 18.