Locomotion is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis. Migration is a complex, multistep process that involves many families of receptors and signaling proteins that eventually impinge on the actin cytoskeleton. Such movement seems to be potentiated and directed by tumor cell–derived cytokines, such as autocrine motility factors. In addition, cleavage products of matrix components (e.g., collagen, laminin) and some growth factors (e.g., insulin-like growth factors I and II) have chemotactic activity for tumor cells. Stromal cells also produce paracrine effectors of cell motility, such as hepatocyte growth factor/scatter factor (HGF/ SCF), which binds to receptors on tumor cells. Concentrations of HGF/SCF are elevated at the advancing edges of the highly invasive brain tumor glioblastoma multiforme, supporting their role in motility.
It also has become clear that the stromal cells surrounding tumor cells are not merely a static barrier for tumor cells to traverse but rather constitute a variable environment in which reciprocal signaling between tumor cells and stromal cells such as fibroblasts and immune cells enable multiple cancer hallmarks (discussed later). For example, a variety of studies have demonstrated that tumor-associated fibroblasts exhibit altered expression of genes that encode ECM molecules, proteases, protease inhibitors, and various growth factors, all of which can influence tumor invasion and extravasation. The most successful tumors may be those that can co-opt the activities of stromal cells to their own nefarious purposes.
Vascular Dissemination and Homing of Tumor Cells
Because of their invasive properties, tumor cells frequently escape their sites of origin and enter the circulation. It is now recognized from studies of “liquid biopsies,” blood samples taken from patients with solid tumors, that millions of tumor cells are shed daily from even small cancers; hence both tumor cells and tumor-derived DNA can be detected in circulation. Most of these tumor cells circulate as single cells, while others form emboli by aggregating and adhering to circulating blood elements, particularly platelets.
Given the ease with which tumor cells access the circulation, it is apparent that the ability of cancers cells to leave the circulation, invade, and grow to clinically significant sizes at other sites in the body is (fortunately for the patient) highly inefficient.
Several factors seem to limit the metastatic potential of circulating tumor cells. While in the circulation, tumor cells are vulnerable to destruction by host immune cells (discussed later), and the process of adhesion to normal vascular beds and invasion of normal distant tissues may be much more difficult than the escape of tumor cells from the cancer. Even following extravasation, tumor cells that have been selected for growth in the originating tissue may find it difficult to grow in a second site due to lack of critical stromal support or because of recognition and suppression by resident immune cells. Indeed, the concept of tumor dormancy, referring to the prolonged survival of micrometastases without progression, is well described in melanoma and in breast and prostate carcinoma. Dormancy of tumor cells at distant sites may well be the last defense against clinically significant metastatic disease.
Despite these limiting factors, if neglected, virtually all malignant tumors will eventually produce macroscopic metastases. The site at which metastases appear is related to two factors: the anatomic location and vascular drainage of the primary tumor, and the tropism of particular tumors for specific tissues. As mentioned earlier, most metastases occur in the first capillary bed available to the tumor, hence the frequency of metastases to liver and lung. Many observations, however, suggest that natural pathways of drainage do not wholly explain the distribution of metastases. For example, prostatic carcinoma preferentially spreads to bone, bronchogenic carcinomas tend to involve the adrenal glands and the brain, and neuroblastomas spread to the liver and bones. Such organ tropism may be related to the following mechanisms: