FEATURE ARTICLE
Metastasis
The spread of cancer cells to distant sites implies a complex series of cellular abnormalities caused, in part, by genetic aberrations
Cornelis J. Van Noorden, Linda Meade-Tollin, Fred Bosman
Sticking Together, Coming Apart
The impact of cellular adhesion in cancer is most clearly manifest in carcinomas—cancers of epithelial cells. Epithelial cells exhibit a rich variety of molecular interconnections. One of these is a very specific cell-membrane structure called the adherence junction. Primarily responsible for the junction is E-cadherin, a large protein that spans the membrane such that one end of the protein pokes out of the cell's surface, while the other end projects into the cell's interior. The external portion of E-cadherin forms interlocking bonds--like the teeth of a zipper—with E-cadherin molecules on neighboring cells. The internal portion hooks into the cell's interior protein skeleton, called the cytoskeleton. Recently, the proteins linking E-cadherin molecules to the cytoskeleton have been identified. These proteins are called catenins.
Before a cell can even start to move about, it first must break this complex, multidimensional interlocking structure. The adherence junction must be disassembled. This might be achieved in one of three ways. First, an alteration in the structure of E-cadherin could be introduced that would prohibit it from forming proper connections. Such an alteration would imply that the gene encoding E-cadherin had become mutated, corrupted in such a way that it encoded a less functional or even a nonfunctional protein. Surprisingly, mutations in the E-cadherin gene are relatively rare.
Second, there could be a decrease in the number of E-cadherin molecules on the cell surface. And, indeed, studies have shown that this is the case in many cancer cells. Finally, the linking proteins—the catenins—might be absent or nonfunctioning. This has in fact been found in an increasing number of cancers. The breakdown of cellular junctions not only diminishes the connections between epithelial cells, but it is also related to the cell's increasing internal disorganization.
It has long been noted that the internal architecture of cancer cells is irregular and disorganized. In general, E-cadherin expression is closely related to cellular differentiation. When they do occur, mutations in the E-cadherin gene often result in poorly differentiated cancer cells whose internal architecture no longer resembles the original structure. Furthermore, the lack of E-cadherin expression alters the relation of cells to each other. The same holds true for catenin mutations.
Of the three forms of catenin molecule, β-catenin has received the most attention. Work in the Johns Hopkins laboratory of Bert Vogelstein has shown that β-catenin not only helps to maintain tissue architecture, it also participates in the cell's internal chemical signaling system. Normally, β-catenin hooks up with another protein called APC (for adenomatous poliposis coli), whose function is to eliminate cells with mutations via apoptosis. A mutation in the APC protein leads to the growth of polyps, small benign tumors in the colon. For people who inherit mutations in APC, the risk is rather large that these polyps will become cancerous.
When acting alone, β-catenin has the potential to initiate cell division. The complex of β-catenin bound to APC prevents this from happening. In this way, cell growth is inhibited. Sometimes one or the other of the proteins in this complex becomes altered—owing to a mutation in the genes encoding them—and the complex cannot be formed. In that case, β-catenin, now unrestrained by APC, interacts with the cell's DNA and activates several genes that cause the cell to re-enter the cell cycle. Abnormal cell growth ensues.
Just as E-cadherins link cells to one another, molecules called integrins link cells to proteins such as collagen in the surrounding connective tissue. Like E-cadherin, the integrins span the cell's membrane, forming connections with connective-tissue proteins outside the cell as well as with proteins in the cell's cytoskeleton, inside the cell. One important difference between normal and cancer cells on the brink of metastasizing is that the cancer cells produce fewer integrins capable of linking with connective tissue than do the normal cells.
Interestingly, not all integrin synthesis stops. On the contrary: In cancer cells integrins are still being produced, but these constitute a set of integrin proteins different from those on normal cells. The so-called invasive cells on their way to becoming metastatic produce integrins that seem to help them migrate through the connective tissue or blood-vessel wall. Specifically, the migratory cells extend cytoplasmic protrusions (like the pseudopods of an amoeba) into the matrix of connective tissue. These protrusions latch on to proteins in the matrix with the help of the new integrin molecules and pull themselves through.
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