Metastasis is the growth of a tumor at a site not physically connected to the primary tumor.
The presence of metastasis is a key feature in determining the prognosis and the treatment strategy for any cancer patient. The probability that a patient will have a metastasis varies widely depending upon the type of cancer. Squamous cell carcinoma of the skin rarely metastasizes, but squamous cell carcinoma of the lung frequently does. An important part of the clinical workup for every patient who is diagnosed with cancer is an evaluation for metastasis. The presence and extent of metastases are a critical component of clinical Staging systems that clinicians use to choose appropriate therapy and to judge prognosis.
Metastases follow different routes that can be broadly classified into three. One is metastasis to the regional lymph nodes or lymphatic metastasis. This involves colonization of draining lymph nodes. The second is travel via open cavities such as the pleural cavity or abdominal cavity (peritoneal metastases). The third is travel through the blood stream or hematogenous metastasis.
Metastasis also has organ specificity. Different types of cancer have characteristic tendencies to metastasize to particular sites. For example, adenocarcinoma of the proximal colon tends to metastasize to the regional lymph nodes within the colon and distantly to the liver. In contrast prostatic adenocarcinoma tends to metastasize to its regional lymph nodes and to the bone. Other cancer types are more promiscuous – for example, breast cancer spreading frequently to the regional lymph nodes, lung, liver, brain, bone, ovaries, and adrenals; or carcinomas of the lung metastasizing, to the lung liver, brain, bone, skin, and adrenals. While metastases are often identified at the time of initial diagnosis, they can also become manifest many years after therapy. This feature of tumor dormancy is particularly notable in breast cancer where metastases can emerge after 10 or 20 years. In many cancer types this long dormancy is less likely.
Cancer is now recognized to be a disease not only consisting of the tumor, but involving the whole organism. Metastasis depends upon properties of the host as well as alterations in the tumor cells. The notion that either the host or the tumor might play a role was first expressed as the soil and seed hypothesis. This frequently cited expression posits that metastasis might be due to alterations in the tumor cell or alternatively to adaptations of the host that now allow the tumor cell to migrate and colonize a distant site. Many years of research now reveal that both mechanisms operate. The study of the molecular changes underlying metastasis is only in its beginnings so that much of the information lacks certainly and detail.
In keeping with the seed hypothesis however are findings showing that the patterns of gene expression in metastatic tumor cells differ from those in nonmetastatic cells. The expression of these genes may help explain organ specificity and may potentially be targets for therapeutic intervention. One question that has been addressed in recent years is to ask whether the gene expression profile of a tumor might predict whether that tumor was likely to have formed metastases. If so the genes involved might also be identified from such a screen. In fact in many studies such gene profiles could be identified, but in general the actual genes identified were not the same in different studies. These profiles are now being refined and additional components such as hypoxia and wound healing profiles are being integrated into the original findings. In some cases the genes found were those made by the host stromal response to the tumor rather than by the tumor itself. Furthermore in comparing metastatic to nonmetastatic tumors in experimental models, the acquisition of new gene expression patterns were clearly seen. Thus the actual situation is more complicated than the original hypothesis that the tumor might express all of the genes needed for metastasis very early in its development. It seems most likely that some of the necessary genes are present early on, but that others are acquired during progression. Finally some of the identified gene products appear to have been synthesized by host responses. Thus host responses may have several roles some of which impede tumor growth, but others that stimulate metastasis.
Invasion is a necessary precursor to metastasis. For the tumor cell reach a distant lymph node or other organ or cavity, it must first separate from the primary tumor mass itself, either as a single cell or as a clump. In vivo imaging in mice has revealed such tumor cell migration through tissue adjacent to the tumor itself. Tumor cells in the blood or lymph then can disseminate. In some systems host cells such as macrophages, fibroblasts and the coagulation system are required for efficient invasion and metastasis, findings in keeping with the soil concept of tumor metastasis.
The microenvironment of a tumor also appears to play a role in metastatic potential. For example hypoxic tumors are more likely to metastasize than tumors with more normal oxygen levels. The infiltrating cells in a tumor may also affect its metastatic potential including fibroblasts, macrophages, and NK cells. For metastasis to the lymph nodes there is some debate about the importance of new host lymphatic channels within the tumor. Recent data raise the exciting hypothesis that the new channels are generated in the lymph nodes themselves.
The contribution by host cells is perhaps most well understood in the formation of bone metastasis in which tumor cells that are successful in establishing themselves in bone synthesize factors such as parathyroid hormone related protein that activate osteoblasts to produce factors such as RANKL that stimulate osteoclasts that release tumor growth factors setting up a complex positive feedback loop. The elements of this loop then form targets for bone metastasis specific therapy.
Thus potential targets for therapy are being identified, many of which will be organ specific. Less clear are the factors that cause tumors to become metastatic in the first place. While genetic mutations clearly drive tumor progression and malignancy, which changes affect metastasis are less clear. Both tumor cell factors and external factors appear to play a role.