I have just arrived from a conference where colleagues at Moffitt’s IMO organised a workshop on computational models of cancer. One of the speakers, Indiana’s James Glazier made a remark that I thought worth passing around. Metastasis, the most important reason why cancers become life-threatening diseases, may not be the result of selection but a byproduct of it.
View from Downtown Miami, where the conference took place.
Metastatic cells have a extremely low success ratio colonising new sites. The vast majority of them never manage to leave the blood or lymphatic vessels that they use to move to different parts of the organism. The few that do, normally end up in sites to which they have not adapted and thus have little hope of colonising properly. Only in rare occasions enough metastatic cells end up in a site that can be invaded successfully (the likelihood of which varies from cancer to cancer).
The conclusion of this is that if you were a tumour cell, there are few chances that having a metastatic phenotype will increase your fitness and, consequently, not many reasons by which metastatic phenotypes could be selected for. The implication, according to Glazier and undoubtedly many others, is that metastasis is not the direct result of selection but a byproduct of a different but related phenotype that does bring an evolutionary advantage to tumour cells that posses it. This could be, for instance, the motile phenotype, which has been proven to give a fitness advantage to tumour cells in many situations. Motile cells will, occasionally stumble into a blood or lymphatic vessel and if this happens a number of times (as the tumour population increases and as the proportion of motile cells over the total does too) then metastasis is likely to eventually happen.
One extra explanation is that when survival in the original site gets tough then it does pay off to be able to metastasise even when the odds are slim. Still, the point of having a high fitness is that fit cells produce more offspring but if the payoff of that higher growth rate happens at a distant site then that is unlikely to be something to be selected for in the original site.
David,
Glad to see you made it back from your road trip. Strangely I was reading this sitting in a group meeting discussing the nature of the cells involved in prostate bone metastasis. A couple of things come to mind, one is that selection for cells that can survive moving is not the same as selecting for cells that can proliferate at their final resting place – which might explain the large number of apparently quiescent metastatic cells that have been described in both breast and prostate cancer patients (and likely others). Perhaps these get out and get somewhere and then get stuck, are able to survive but don’t have an apparatus to allow them to proliferate. So the question becomes do the cells have to have other concurrent, or subsequent, changes that allow them to survive. Or perhaps other stromal cells go along for the ride in rare cases, or end up in the same place by chance, and thus contribute to an environment in which the tumor cells can start to proliferate. It has been suggested that early events at a metastatic site can contribute to survival and more important proliferation at that site. For example an osteolytic reaction, which liberates growth factors, might be required even to establish primarily osteoblastic lesion. So having the equipment to set this up could be important.
OK, better stop typing – back to paying attention to the meeting!
Simon
Metastasis is not the direct result of selection but a byproduct of a different but related phenotype that does bring an evolutionary advantage to tumour cells that posses it.
I like that statement. It does for exampe explain that we have identified about 1000 genes involved in the cancer phenotype, but not more than 10 genes that are specifically involved in the metastatic process.
Simon, I agree that selection for motility is not selection for metastasis and thus is the more remarkable that one thing can lead to the other. The idea is that in a heterogeneous enough tumour there will be enough motile cells that not necessarily the same. That is, several phenotypes that still share the fact that are motile. When there’s enough motility and heterogenicity to go around then there’s a better chance that one of the escaping cells will have the right phenotype to colonise a new location, just by chance, the more you play the bigger the likelihood of winning.
I also like the hypothesis that tumour cells carrying with them a bit of their original microenvironment (such as a few stromal cells) have a bigger chance of success in colonising a new site.
Martin, you have just mentioned one of the reasons why I think that we need more work done in understanding cancer phenotypically as this is the level at which evolution works.
“Metastasis, is one of the most importants why cancers become life-threatening diseases, may not be the result of selection but a by product of it” what David Basant said in his blog cancerevo; Evolution and Cancer at Nature.com. But metastasis is the end product of an evolutionary process in which diverse interactions happens continuously between cancer cells and their microenvironment and yields alteration that helps these metastatic cancer cells to express their programmed behavior and survive. Metastatic tumor cells thus doubles or triples in n numbers , proliferate and flourish in new times habits and ultimate cause of organ dysfunctions where they lodge and cause death. The prime tumor consists of heterogeneous population of cells with genetic alteration that allow them to surmount physical boundaries, disseminate and colonize at a distant organ. The intrinsic genomic instability to cancer cells increases the frequency of alterations necessary to acquire metastatic capacity. The genomic instability and heterogeneity of tumor cells are found apparent through either chromosomal gain, chromosomal losses and chromosomal rearrangements [ philadelphia chromosome for example] associated with cancer cells DNA integrity that can be compressed by aberrant cell cycle, progression, telomeric crisis[ prostate cancer for example], inactivation of DNA repair genes and altered epigenetic control mechanism. The epigenome is today emerging as a major factor contributing to both a malignant tumor formation and its progression. It is affecting oncogene and tumour suppressor gene expressions and the epigenetic genes may be thus potential sites for targeting for cancer therapy.
The Most common other associated mechanisms that metastasis occurs are 1) loss of E Cathedrin molecule for cell adhesion and various mechanisms like gene mutation, gene silencing by promoter gene methylation, down regulation stimulated by growth factor receptors, like fibroblast growth factor receptors, insulin like growth factor receptors are responsible for loss of E cathedrin molecules from the environments of metastatic cancer cells. IGF pathway – specifically the insulin-like growth factor 1 receptor (IGF-1R) can be thus targeted for cancer therapy as an adjuvant therapy. Expression of E cathedrin gene is also inhibited by several other transcriptional receptors. such as translation initiation and cap-dependent translation m Tor that cause downstream of IGF
There is presence of gene for metastasis . Presence of metastasis gene in gene expression signatures of primary tumors is found to challenge the traditional tumor progression model of somatic evolution in which metastatic cells will be to influence a population. Metastatic progression genes are many. To mention MMP1, COX2 genes for breast cancer and lung metastasis for example. These genes co operate in remodeling the vasculature sites of mammary tumor and lung parenchyma metastasis. In Breast carcinoma they allow neo angiogenesis and invasion of cancer cells. In the lung they mediate Extravasion of circulating cancer cells from capillaries into parenchyma.
Hypoxia of tumor cells are another factor for progression of metastasis. Hypoxia causes release of Hypoxia Inducible factor (HIF) which is released from a programmed gene expression that leads to changes in anaerobic metabolism, angiogenesis, invasion & survival of metastatic clone of cells. HIF boosts expression of Lysyl oxidases enzymes. Lysil Oxidase regulates the activity of local adhesion kinases in way they enhances cell matrix adhesion & invasion. High level of Lysyl Oxidase thus correlates with shorter metastasis free survival and poor prognosis in head and neck and prostate cancers as well as in estrogen negative breast cancers. Another product of HIF induced gene activation, the chemokine(Cx-C motif) receptor CxCR4 with its ligands the Chemokine stromal cell derived factor-19SDF-1) also called CXC chemokine ligand12(CXCL12) facilitates both survival and the movement of cancer cells to sites of Metastasis.
Another signaling pathway for aggressive metastasis of cancer cells is that of EGFR and Notch pathway. The nuclear EGFR pathway might be associated with more aggressive tumors, as it is involved in increasing proliferation and accelerating cell cycle progression.
Professor Pranab kumar Bhattacharya
Professor of Pathology IPGME&R kol-20 ; Miss Upasana Bhattacharya and Mr. Rupak Bhattacharya Bsc(cal) Msc(JU) of 7/51 purbapalli; Po= Sodepur Dist 24 parganas(north) Kol-110, Dr. Tridib MandalAsst. Professor of Biochemistry, IPGME&R,kol-20; Mrs. Dalia Mukherjee BA Cal. and Mr. Debasis Mukherjee Bsc (cal) swamiji Nagar South Habra ,West Bengal andwww.unipathos.com
© To Prof Pranab Kumar Bhattacharya as per IPR Copy Right Rules
Dear Pranab Kumar Bhattacharya, thanks for your contribution and thanks for discussing all these metastasis associated cellular mechanisms.