Cell competition and selection as a driver of malignant progression
we’re experiencing the era of tumor environment appreciation in cancer research. Cancer progression is not cell autonomous! It depends so much on the environmental context. But to complete a picture, please take into account a competition between cancer and normal cells for their environment.
Cell competition as a biological phenomenon has been studied for the last 30 years. But only recently in mammals and very recently in stem cell biology. I’ll try briefly to summarize the role of cell competition in cancer progression, including stem cell.
What cells could compete with each other?
- Normal cells could compete for organ integrity in development and normal tissue turnover
- Normal stem cells could compete with each other for occupancy of the niche
- Finally, cancer cells could compete with normal cells for environment in order to progress
Cell competition in normal conditions
Cell competition for the first time was discovered in Drosophila:
Cell competition, a well-recognized phenomenon of cell-cell interaction, was first discovered in Drosophila wing imaginal discs, where growth-disadvantageous cells are eliminated by wild-type cells, which subsequently undergo compensatory proliferation to maintain proper disc size.
What is the biological meaning of cell competition in the normal organism?
Imagine this: on the planet Earth (multicellular organism) people (cells) live in cities or communities (tissues), forming more complex structures – countries (organs). Because members of these communities could be socially unequal, they need some sort of control (law) or “moral principles” if you will, in order to maintain integrity. This is a principle of cell competition in normal multicellular organism, guys.
Cell competition as a mechanism to maximize tissue fitness:
Cell-autonomous apoptosis is enough to kill cells that have major functional problems. However, if the cell that the multicellular animal wants to get rid of is viable, another discriminatory step is required to identify such suboptimal cells. The fact that all initial examples of cell competition resulted in wild-type cells being the winners led to the proposal that cell competition may be an efficient mechanism to maximize tissue fitness and optimize organ function, ensuring that viable but suboptimal cells do not accumulate during development or ageing.
So, cell competition seem to be responsible for maintainance of tissue integrity in a multicellular organism. One more important definition – cell fitness:
… “fitness” is a measure of the ability of a cell of a certain genotype to pass this genotype to subsequent cell generations, as governed by competition for similar niches.
Cell competition in malignant progression – lessons from Drosophila
Cell competition in cancer progression could occur on different levels:
- cancer non-stem cell versus normal cells
- cancer stem cells versus normal stem cells
Competition between cancer cells and normal cells was described very well in Drosophila:
What if a transformed cell could proliferate without producing morphological malformations, because the increase in cell number was balanced by the apoptotic elimination of surrounding cells and, therefore, the total cell number did not change? An intriguing phenomenon in D. melanogaster known as ‘cell competition’ has been described to do just this: cells proliferate by killing surrounding wild-type cells by apoptosis so that the total cell number does not change. As a consequence, clonal expansion did not generate morphological aberrations and the growth of these cells passed unnoticed.
At least two types of mutations, which can trigger cell competition in cancer development, were identified in Drosophila – d-Myc and Hippo pathway:
A two- fold increase in DMYC levels is enough to transform cells into super-competitors
As Myc family genes are prominently involved in human cancers and there is increasing evidence that Hippo pathway components are deregulated in human tumours, super-competition has been hypothesized to be involved in the early stages of cancer formation.
I’d like to point out two very Interesting biological phenomena associate with cancer cell competition described in drosophila that are nicely summarized in this review:
- Clonal expansion upon competition required killing of neighbouring cells. Therefore cancer cell competition is very early event of malignant development and due to initial absence of tissue growth could be undetectable. So, apoptosis could have a dual role in carcinogenesis: (i) inhibition to promote self-survival and proliferation and (ii) killing of surrounding competitors.
- On one hand, overexpression of some genes could transform cells into super-competitors, leading to malignant progression (d-Myc, Hippo pathway). But, on the other hand, overexpression of such gene as Minute, involved in cell competition, can not drive competition above normal levels.
Stem cell competition for niche occupancy
Despite very nice work on Drosophila, we still don’t know how cell competition occurs in mammals. But there are some evidence that cell competition in adult mammals occurs on the level of somatic (tissue) stem cells and their niches. Natural (Darwinian) selection and phenotypic evolution through competition of stem cell for the niche was nicely modeled by Marc Mangel in 2008:
… in healthy organisms, we should not expect the stem populations to be at their maximum sizes.
To understand fully how natural selection acts on a stem cell, we need to consider the fitness of a focal stem cell. Stem cells (and transit amplifying cells) do not by themselves achieve fitness. Rather, they support the organism – which can be viewed as an organized collection of fully differentiated cells. Fitness of the focal stem cell depends upon what it does, what the other stem cells in the niche do, and how many transit amplifying and differentiated cells are present.
Hematopoietic stem cells (HSC) re-circulate and compete for their niches in normal steady-state conditions as well as in bone marrow transplantation settings. In order to assess HSC fitness and competition, bone marrow transplant should be done:
… marrow engraftment is determined by stem cell competition indicates that final donor chimerism after transplant is directly related to the ratio of donor to residual host stem cells.
Leukemic stem cell competition for bone marrow niches
Competitive repopulation assay in experimental bone marrow transplantation allows to identify gene-candidates or mutations associated with high (cells-winners) or low (cells-losers) or super-high (cells-cheaters) stem cell fitness. Loss of tumor-suppressor genes, such as p53, in competitive settings could generate HSC-winners and cheaters. Later it could lead to clonal selection, expansion and leukemogenesis. Interestingly, unlike Drosophila, HSC-losers undergo senescence, but do not get killed by winners via apoptosis:
We propose that p53-mediated stem cell-specific, senescence-like response to DNA damage operates as a “memory of past damage”: while still compatible with proliferation, it permanently marks HSPCs that have experienced DNA damage and thus promotes their gradual replacement by undamaged cells over time, if such cells are available.
In my recent post about Bondar-Medzhitov study , I noted:
… most importantly, this work provided evidence for carcinogenesis (irradiation)- induced selection. It contradicts the assumption that oncogenic mutation alone caused by carcinogenic factor can initiate the malignant process (mutagenesis versus selection). It is also important that this selection occurs in context of stem cell niche and can give us a clue of how neoplastic process is initiated and progresses.
Not only loss of p53, but such oncogenic mutations as Bcr-Abl can give competitive advantage to hematopoietic progenitor cells and cause age-associated leukemogenesis:
… Bcr-Abl provides a much greater competitive advantage to old B-lymphoid progenitors compared with young progenitors, coinciding with restored kinase signaling pathways, and that this enhanced competitive advantage translates into increased promotion of Bcr-Abl-driven leukemias. Moreover, impairing IL-7-mediated signaling is sufficient to promote selection for Bcr-Abl-expressing B progenitors. These studies support an unappreciated causative link between aging and cancer: increased selection of oncogenic mutations as a result of age-dependent alterations of the fitness landscape.
This is actually the first study which demonstrates competition of progenitor cells (B-cell progenitor) for environment (IL-7 signaling) in context of aging. Interestingly, young normal hematopoietic progenitors beat co-transplanted Bcr-Abl-expressing cells in competition for rescue of IL-7 signaling and normal B-cell lymphopoiesis.
The role of malignant cell competition in bone marrow niches was elucidated in some human hematological malignancies.
Genome-wide analysis unveils the secret of leukemia relapses
Acute lymphoblastic leukemia (ALL) affects people of all ages with a sharp peak of incidence among children ages 2 to 3. After decades of dedicated basic and translational research, the cure rate of ALL is as high as 80%. However, 20% of ALL patients undergo relapse after the initial chemotherapy regimen.
Thanks to the emerging modern high throughput methods which provide us a chance to take a full-scale look at the profile of those mysterious liquid tumor cells. Genomic-wide analysis was performed on 242 ALL patients. The results revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases.
The authors asked the next question - how are those genome abnormalities related to the relapse of ALL? What the researchers did was to collect matched pairs of samples from diagnosis and relapse ALL and took a close look at their genomic changes. If you are expecting further evolutionary ALL cells in the relapse samples, you will be disappointed.
What they found was that cells responsible for relapse are ancestral cells to primarily diagnosed ALL in as high as 51% out of 61 patients. The diagnosis and relapse samples typically showed different patterns of genomic copy number abnormalities (CNAs). Moreover, the CNAs acquired at relapse preferentially affect genes that fall into the category of cell cycle regulation and B cell development.
Clonal relationship of diagnosis and relapse samples in ALL. The majority of relapse cases have a clear relationship to the diagnosis leukemic clone, either arising through the acquisition of additional genetic lesions or, more commonly, arising from an ancestral (prediagnosis) clone. In the latter scenario, the relapse clone acquires new lesions while retaining some but not all of the lesions found in the diagnostic sample. Lesion-specific backtracking studies revealed that in most cases the relapse clone exists as a minor subclone within the diagnostic sample before the initiation of therapy. In only a minority of ALL cases does the relapse clone represent the emergence of a genetically distinct and thus unrelated second leukemia.
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