The stroma provides a framework for the tumor. It is composed of normal connective tissue containing fibroblasts and inflammatory white blood cells, as well as the endothelial cells that form blood and lymphatic vessels with their attendant pericytes and smooth muscle cells (Figure 20–15). As a carcinoma progresses, the cancer cells induce changes in the stroma by secreting signal proteins that alter the behavior of the stromal cells, as well as proteolytic enzymes that modify the extracellular matrix. The stromal cells in turn act back on the tumor cells, secreting signal proteins that stimulate cancer cell growth and division as well as proteases that further remodel the extracellular matrix. In these ways, the tumor and its stroma evolve together, like weeds and the ecosystem that they invade, and the tumor becomes dependent on its particular stromal cells. Experiments using mice indicate that the growth of some transplanted carcinomas depends on the tumor-associated fibroblasts and normal fibroblasts will not do. Such environmental requirements help to protect us from cancer, as we discuss next in considering the critical phenomenon called metastasis.
Cancer cells generally need to spread and multiply at new sites in the body in order to kill us, through a process called metastasis. This is the most deadly—and least understood—aspect of cancer, being responsible for 90% of cancer-associated deaths. By spreading through the body, a cancer becomes almost impossible to eradicate by either surgery or local irradiation. Metastasis is itself a multi-step process: the cancer cells first have to invade local tissues and vessels, move through the circulation, leave the vessels, and then establish new cellular colonies at distant sites (Figure 20–16). Each of these events is complex, and most of the molecular mechanisms involved are not yet clear.
For a cancer cell to become dangerous, it must break free of constraints that keep normal cells in their proper places and prevent them from invading neighboring tissues. Invasiveness is thus one of the defining properties of malignant tumors, which show a disorganized pattern of growth and ragged borders, with extensions into the surrounding tissue (see, for example, Figure 20–8). Although the underlying molecular changes are not well understood, invasiveness almost certainly requires a disruption of the adhesive mechanisms that normally keep cells tethered to their proper neighbors and to the extracellular matrix. For carcinomas, this change resembles the epithelial–mesenchymal transition (EMT) that occurs in some epithelial tissues during normal development (see p. 1042).
The next step in metastasis—the establishment of colonies in distant organs— begins with entry into the circulation: the invasive cancer cells must penetrate the
Figure 20–15 The tumor microenvironment plays a role in tumorigenesis. Tumors consist of many cell types, including cancer cells, endothelial cells, pericytes (vascular smooth muscle cells), fibroblasts, and inflammatory white blood cells. Communication among these and other cell types plays an important part in tumor development. Note, however, that only the cancer cells are thought to be genetically abnormal in a tumor.
1102 Chapter 20: Cancer normal epithelium cells grow as benign tumor in epithelium cells become invasive and enter capillary (fewer than 1 in 1000 cells will survive to form metastases) adhere to blood vessel escape from blood vessel colonize liver, forming wall in liver to form micrometastasis full-blown metastasis
Figure 20–16Steps in the process of metastasis. This example illustrates the spread of a tumor from an organ such as the bladder to the liver. Tumor cells may enter the bloodstream directly by crossing the wall of a blood vessel, as diagrammed here, or, more commonly perhaps, by crossing the wall of a lymphatic vessel that ultimately discharges its contents (lymph) into the bloodstream. Tumor cells that have entered a lymphatic vessel often become trapped in lymph nodes along the way, giving rise to lymph-node metastases.