What makes some tumors spread whereas others stay benign?
Tumor cell spreading is a multistep cell-biological process that is initiated by the local invasion of epithelial cells from the primary tumor into the surrounding extracellular matrix (ECM) and stroma. This invasion is followed by intravasation of the tumor cells into blood and lymph vessels for transportation through the vasculature and subsequent seeding at distant metastatic sites. These complex biological processes are orchestrated by molecular pathways operating within the cancer cells (intrinsic factors) or by signals originating from non-neoplastic stromal cells communicating with cancer cells (extrinsic factors).
For individual or clusters of epithelial cancer cells to break away from the primary tumor and invade locally into the stroma, the cells must acquire the ability to migrate and invade. This task is not easy because the epithelial cells are tightly bound to neighboring cells and to the underlying basement membranes by adherens junctions, tight junctions, desmosomes, and hemi-desmosomes, effectively immobilizing them. Because of these physical constraints, at the early stages of primary tumor expansion, the cells are not invasive and metastatic.
As the tumor progresses, however, cancer cells can acquire a sequence of genetic and epigenetic alterations that confer invasiveness and metastatic ability to the tumor cells, allowing them to switch on certain intrinsic programs to liberate themselves from these restricting associations. Nonmetastatic cells (i.e. cells forming benign tumors) do not acquire these genetic and epigenetic alterations, hence they are not able to metastasize.
Examples of genes that could be altered in order for cells to gain a metastatic phenotype include (1) genes controlling cytoskeletal rearrangements (e.g., Rho GTPase’s Rho A and Rho C, which control the actin cytoskeleton, have been shown to be overexpressed in some metastatic cancers); (2) genes encoding for proteases (such as cathepsins and matrix metalloproteinases) that can degrade the basement membrane, a specialized ECM that separates the epithelial and stromal compartments; destroying the basement membrane allows cancer cells to invade locally into the surrounding stroma; and (3) genes that regulate angiogenesis such as vascular endothelial growth factors (VEGFs)that can promote formation of new blood vessels (neoangiogenesis) within the tumor microenvironment. It has been shown that in contrast to blood vessels present in normal tissues, the neovasculature generated by carcinoma cells is disorganized, prone to leakiness, and in a state of continuous reconfiguration, which facilitates tumor cell intravasation.
The tumor microenvironment (TME) also plays a role in tumor cell invasion and metastasis. The TME is made up of various cell types such as fibroblasts, myofibroblasts, granulocytes, mesenchymal stem cells, lymphocytes, and macrophages. Most of these cells (e.g., macrophages) normally have an antitumorigenic role. However, because of the myriad of mutations that cancer cells progressively accumulate, cancer cells can acquire the ability to “hijack” these cells and use them for their own advantage, essentially reprogramming them to assume protumorigenic roles instead. For example, signaling between stromal cells and cancer cells can activate the epithelial-to-mesenchymal transition (EMT) program in cancer cells. EMT describes a rapid modulation of phenotype by epithelial cells. Epithelial cells loosen cell-cell adhesion structures, including adherens junctions and desmosomes; modulate their polarity; and rearrange their cytoskeleton, with the cells becoming isolated and motile. Hence, epithelial cells that have undergone EMT acquire a more migratory/metastatic phenotype.
More ways that stromal cells could promote invasiveness of metastatic cancer cells is by secretion of angiogenic factors such as VEGFs, promoting neoangiogenesis; secretion of proteases that degrade ECM-promoting cell motility; and secretion of chemotactic factors that can attract cancer cells toward blood vessels, thereby promoting cancer cell intravasation.
In summary, the reason why metastatic cancers spread and benign tumors don’t is because metastatic cancers have acquired genetic and epigenetic modifications that benign tumors don’t have. These alterations not only switch on various programs within the cell that control the invasiveness and metastatic ability of the cells but also enable the cells to recruit and communicate with stromal cells and use them as accessories to the metastatic cascade. The combination of intrinsic programs operating within cancer cells and extrinsic programs emanating from cellular components of the tumor microenvironment is what makes metastatic cells spread.
1. Valastyan, S., and Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292.
2. Yokota, J. Tumor progression and metastasis. Carcinogenesis 21:497–503.
3. Chaffer, C. L., and Weinberg, R. A. A perspective on cancer cell metastasis. Science 331:1559–1564.
4. Sahai, E. Illuminating the metastatic process. Nat. Rev. Cancer 7:737–749.
5. Thiery, J. P., and Sleeman, J. P. Complex networks orchestrate epithelial mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7:131–142.