|Clonal evolution during in situ to invasive breast carcinoma progression1|
What’s a tumor?
In some ways, that’s a bad question (never mind the answer) because it implies that a tumor is a single thing. But we know that’s not true. A tumor, by the time we can detect it, is a collection of many cells, at least billions of them, and those cells are not all the same. I’m not even talking about the normal cell types that are incorporated into a tumor (things like blood vessels and support cells). Even cells that are unambiguously cancerous are very different within a tumor. And of course, that’s important for the things we’re most interested in, prognosis and treatment, because it’s not the average tumor cell that we’re most concerned about, it’s the subset of tumor cells that are most resistant to treatment, or that are most aggressive.
The development of this variation is really fundamental to how we understand tumor formation and tumor growth. Cancerous cells don’t just appear, fully ready to metastasize and grow. What happens is that a normal cell mutates slightly and gains a little advantage. Most of its progeny stay like that, but one of them mutates again and changes a little more, and then one of that cell’s progeny mutates again, and so on. It probably takes at least a half-dozen mutations, over many cell generations, before a normal cell has progressed through to a detectably cancerous cell. (I’ve talked about this before, here.)
Also, since truly normal cells simply don’t mutate that many times — there are too many checks and repair systems to allow a half-dozen mutations to accumulate in a single human’s2 lifetime — one of the mutations is probably in the check/repair system, turning the cancerous pathway into a mutator pathway as well.
So we expect tumors to be made up of many different cell types, and this is indeed what we see:
With rare exceptions, human malignancies are thought to originate from a single cell, yet by the time of diagnosis, most tumors display startling heterogeneity in cell morphology, proliferation rates, angiogenic and metastatic potential, and expression of cell surface molecules. 1
So how diverse are tumors?
That’s been a hard question to answer, because you’d need tools to look at individual cells, and you’d also need some way of expressing that diversity. A recent paper1 looked at diversity in breast cancer using some individual-cell tools, which I’m not going to discuss, and took an interesting approach to describing the variability:
… we applied diversity measures from the ecology and evolution sciences to our copy number data. These diversity measures estimate the number and distribution of species in a certain geographical area or environmental niche. In our context, a species is a cancer cell population … Hence, a region of a tumor containing cancer cells with 3 different copy number ratios is interpreted to contain 3 distinct “species.” 1
They suggest that this way of describing tumors could be a useful aid to prognosis and to predicting response to therapy, offering a quantitative description of tumor variability (which might correlate with the tumor’s potential for spread and escaping treatment).
I hadn’t thought of tumors as ecosystems before, but I wonder if the analogy could be taken further by considering, say,cytotoxic T lymphocytes as predators …