Invasion and metastasis, the most insidious aspects of cancer, are the major causes of cancer treatment failure. In human patients with cancer, it is estimated that approximately 30% of individuals with newly diagnosed solid tumors (excluding non-melanoma skin tumors) already have clinically detectable metastases. Of the 70% of patients clinically free of metastasis, approximately one-half can be cured by local therapy alone. The remaining patients have clinically occult micrometastases which, left untreated, will grow and metastasize. Thus, 60% of patients have microscopic or clinically evident metastasis at the time of primary tumor treatment.
A metastatic colony is the end result of a series of host-tumor interactions. Primary tumor initiation and promotion are followed by progressive growth of neoplastic cells. The malignant cell population must promote angiogenesis to grow beyond a few millimeters in diameter, and indeed, it is suspected that progressive tumor growth is angiogenesis-dependent. A variety of angiogenic agents effect vascular proliferation. These agents cover a wide range of molecular weights, from large molecules such as Fibroblast Growth Factor to small Endothelial Cell Angiogenic Factors. At least seven angiogenic peptide genes have been sequenced and cloned. Newly formed blood vessels are often defective and easily invaded by tumor cells within the primary tumor mass, and as the tumor infiltrates, pre-established blood vessels are also invaded. Tumor cells enter the circulation, most commonly through thin-walled venules and lymphatics and appear in the blood stream in clumps or as single cells. For rapidly growing tumors 1 cm in diameter, millions of tumor cells can be shed into the circulation every day, but fortunately, only a very small percentage of circulating cells initiate metastatic colonies.
Circulating tumor cells arrest in the capillary beds of organs by attaching directly to intact endothelial surfaces or to exposed subendothelial basement membranes. Clumps of tumor cells or tumor cells aggregated with leukocytes, fibrin or platelets can embolize directly into the precapillary venules by mechanical impaction. Tumor cells adhering to surface endothelium rapidly induce active retraction of the endothelial cells and avidly adhere to the exposed basement membrane. Once the tumor cells have attached to the basement membrane, the endothelium will extend over the tumor cell and separate it from the bloodstream.
Invasion of the basement membrane is an active process that involves several steps. For all invasion barriers, tumor cells require some type of initial firm binding for penetration, but the actual receptor or integrin/matrix molecule interactions involved are likely to differ at different sites. After attachment, the tumor cells secrete hydrolytic enzymes which can locally degrade the matrix. Tumor cell pseudopodia in the region of the matrix modified by proteolysis then allows the tumor cell to traverse the basement membrane. Metalloproteinases are degradative enzymes released by tumor cells. There are 3 metalloproteinases associated with dissolution of the basement membrane components collagen and laminin; type I collagenase, type IV collagenase and stromelysin. Cellular adhesion to laminin is required to enable tumor cells to traverse the basement membrane, whereas interaction with fibronectin may be important during invasion of the stromal matrixes. The metalloproteinases are normally regulated by tissue inhibitors.
For the tumor cells to proliferate within the target organ parenchyma, extravasated tumor cells use autocrine growth factors or growth factors from the local tissue or circulation. These metastatic colonies must develop a vascular network to produce detectable lesions. At all stages of the metastatic cascade, the tumor cells must overcome host defenses. Malignant tumors resist destruction by the immune system by secretion of growth factors that inhibit immune functions, shedding of antigens, and perhaps defective major histocapatability complex (MHC) gene expression.
The site distribution of metastases depends upon the histologic type and anatomic location of the primary neoplasm. Approximately one-half of metastases can be predicted by anatomic considerations, and the most frequent site of the metastasis is the first capillary bed encountered by the circulating tumor cells. Thus, sarcomas metastasize to the lungs and gastrointestinal tumors spread to the liver. Nearly 40% of metastatic colonies, however, cannot be predicted on the basis of anatomic considerations.
From a clinical perspective, there is a great need to be able to understand the factors contributing to local tumor invasion and metastasis. This information would be used to predict the aggressiveness of a tumor within an individual patient; allow methods to be developed for detection of clinically occult micrometastases; and allow the development of strategies to eradicate established metastases.