In a recent paper by Hanahan and Weinberg ( Hallmarks ofCancer: The Next Generation, Cell, 2011) has some interesting observations on what has been developed in the area of cancer research. As they state at the outset:
The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list—reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the ‘‘tumor microenvironment.’’
Another dimension of complexity is not represented in this simple schematic: both neoplastic cells and the stromal cells around them change progressively during the multistep transformation of normal tissues into high-grade malignancies. This histopathological progression must reflect underlying changes in heterotypic signaling between tumor parenchyma and stroma. Such stepwise progression is likely to depend on back-and forth reciprocal interactions between the neoplastic cells and the supporting stromal cells, …. Thus, incipient neoplasias begin the interplay by recruiting and activating stromal cell types that assemble into an initial preneoplastic stroma, which in turn responds reciprocally by enhancing the neoplastic phenotypes of the nearby cancer cells.
The cancer cells, which may further evolve genetically, again feed signals back to the stroma, continuing the reprogramming of normal stromal cells to serve the budding neoplasm; ultimately signals originating in the tumor stroma enable cancer cells to invade normal adjacent tissues and disseminate. This model of reciprocal heterotypic signaling must be extended to encompass the final stage of multistep tumor progression—metastasis ...
The circulating cancer cells that are released from primary tumors leave a microenvironment created by the supportive stroma of such tumors. However, upon landing in a distant organ, these cancer cells encounter a naive, fully normal, tissue microenvironment. Consequently, many of the heterotypic signals that shaped their phenotype while they resided within primary tumors may be absent in sites of dissemination, constituting a barrier to growth of the seeded cancer cells. Thus, the succession of reciprocal cancer cell to stromal cell interactions that defined multistep progression in the primary tumor now must be repeated anew in distant tissues as disseminated cancer cells proceed to colonize their new found organ sites.
The model presented can be reduced to some simple descriptions, albeit a major change from a decade prior. The model is shown below:
Note that we have two different steps. The classic first step, the Vogelstein model, takes the normal cell via some genetic change into a cancer cell. The model here requires some genetic change where loss of the control mechanism for growth or death are altered. Understanding normal pathways we can see that if we lose a genetic element associated with some pathway we can lose the control elements which would result in a cancerous cell. However that does not in and of itself lead to a metastatic type of cancer, it may merely lead to a cell which grows more than it should.
When we examine the cancer cell we see a multiple set of pathways and a corresponding multiple set of means in which the pathway control of homeostasis can be degraded to create a cancer cell. We show such a model below which is a modification of what the author’s present.
This model is an example of the classic pathway models which we have discussed earlier . Each of the pathways are triggered by some external stimulus and one often wondered what happened to do this.
To answer this question is the context of a larger model the authors report on a volume of research which they have been doing every ten years. One of the interesting elements is the development of a multicellular control mechanism after a malignancy has developed. To do this the authors consider first a collection of interacting cells and second the signalling mechanism which are used between the cells.
The authors first consider six cell classes. They are:
1. Cancer Cells – all the developing cancer cells
2. Bone Marrow – cells in the bone marrow
3. Tumor Promoting Inflammatory Cells
4. Endothelial Cells – thin layer of cells inside the blood vessels
5. Pericytes – connective tissue cell in blood vessels
6. Fibroblasts – generates the intercellular fabric
Now the cells communicate via the following signalling proteins, each with its receptor. They are:
1. EGF- Epidermal Growth Factor attached to EGFR (receptor) and initiates cell growth.
2. HGF – Hepatocyte Growth Factor acts on endothelial cells and other cells
3. PDGF – Platelet Derived Growth Factor for blood vessel formation and is also a powerful mitogen.
4. VEGF – Vascular Endothelial Growth Factor produced by blood vessels and induces growth of new endothelial cells.
5. TGF-β – Tumor Growth Factor stimulates cell growth and tumor growth.
6. IL-1βapoptosis.
7. Ang-1 – Angiopoetin 1 promotes angiogenesis
8. CXCL-12 – Chemokine Ligand 12, This gene product and its receptor CXCR4 can activate lymphocytes and have been implicated in the metastasis of some cancers such as breast cancer.
9. Protease - involved in angiogenesis
10. CSF-1 – Colony Stimulating Factor 1 a cytokine that controls the production, differentiation, and function of macrophages
We depict the result below:
Now we can reduce the above graphic to a system model which we show below. Here we show cells and driver stimuli from cell to another cell. We have a very complex network where the start of the process is the genetic change in a normal cell which becomes a cancer cell.
We can now look at the dynamics of this complex process. We can specify for example the concentrations of the products or cells as follows:
Now one must remember that if we have no cancer cells then the process may continue without a malignancy. However if the cancer cell is developed then this model may represent the development of the cancer in the related micro environment.
Thus we can state:
The matrix A relates the links which have been described. Inherent in this is also the reaction rate dynamics which we have linearized.
Now the process may go as follows:
1. In a benign state there is no cancer cell so that the system functions with the initial condition being zero for cancer cells.
2. Apart from the cycle, something happens inside a normal cell to alter its internal pathways, say from a genetic change, a methylation, some microRNA or the like.
3. This change then alters, activates, or deactivates a set of pathways which now can thrive in this environment.
4. The environment then becomes a positive feedback factor in the growth and dissemination of the cancer cells.
There are many interesting questions which may arise from this view. First the body itself propagates the cancer cells. Thus rather than just attacking the cancer cells we may consider attacking or modifying this supportive environment.
The authors conclude:
Yet other areas are currently in rapid flux. In recent years, elaborate molecular mechanisms controlling transcription through chromatin modifications have been uncovered, and there are clues that specific shifts in chromatin configuration occur during the acquisition of certain hallmark capabilities …. Functionally significant epigenetic alterations seem likely to be factors not only in the cancer cells but also in the altered cells of the tumor-associated stroma. It is unclear at present whether an elucidation of these epigenetic mechanisms will materially change our overall understanding of the means by which hallmark capabilities are acquired or simply add additional detail to the regulatory circuitry that is already known to govern them.
Similarly, the discovery of hundreds of distinct regulatory microRNAs has already led to profound changes in our understanding of the genetic control mechanisms that operate in health and disease. By now dozens of microRNAs have been implicated in various tumor phenotypes … and yet these only scratch the surface of the real complexity, as the functions of hundreds of microRNAs known to be present in our cells and altered in expression in different forms of cancer remain total mysteries. Here again, we are unclear as to whether future progress will cause fundamental shifts in our understanding of the pathogenetic mechanisms of cancer or only add detail to the elaborate regulatory circuits that have already been mapped out.
Finally, the circuit diagrams of heterotypic interactions between the multiple distinct cell types that assemble and collaborate to produce different forms and progressively malignant stages of cancer are currently rudimentary. In another decade, we anticipate that the signaling circuitry describing the intercommunication between these various cells within tumors will be charted in far greater detail and clarity, eclipsing our current knowledge. And, as before … we continue to foresee cancer research as an increasingly logical science, in which myriad phenotypic complexities are manifestations of a small set of underlying organizing principles.
The three points in their conclusion are worth merit:
1. Epigenetics and the complexity of reactions
2. Micro RNAs and their overall influence
3. Heterogeneous pathway dynamics, as we have outlined, and their complexity.
The major effort to date was to understand intracellular pathways. Now we can combine them with extracellular, or spatial pathways. This reminds us again of the work by Turing, the old zebra stripe issue.
Micro RNA and epigenetics can become an issue akin to adding noise but what type. Their behavior is more akin to randomness at least as is currently understood.
Having these papers provides a wonderful baseline worth reviewing a decade at a time.
Posts
