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Physical oncology PO is defined as the study of the role of mechanical signals in a cancerous tumor. If we generalize we will speak of " stress field " and " stress tensor ". A cancerous tumor or "solid tumor" in the jargon of oncologists to differentiate them from hematological malignancies is an organ consisting of two tissues: in the center the cancerous tumor proper and around the ExtraCellular Matrix ECMsometimes called stroma, chorion or connective tissue. The concept of connective tissue is interesting because it defines a tissue that travels the entire organism except the brain and is a preferred transmitter of mechanical signals.
But for the cancer organ - isolated from this connective system - we prefer the term ECM. The cancerous tissue is derived from a normal tissue of the body: breast cancer arises from a cancerous transformation of the normal mammary glandular tissue.
It looks more or less like the original tissue: it is said that it is more or less differentiated; poorly differentiated it has a microscopic appearance that is far from normal tissue and is then "poorly prognostic", will make more metastases and will be more difficult to treat.
We are only considering cancers derived from "epithelia", that is to say the tissue that covers the organs in their interfaces with air, liquids or the outside world.
Epithelial cells are contiguous and polarized. arise from these epithelia after a long process of cancerization. ECM is a mixture of cells immune, fibroblastsetc. dispersed in proteins, most of them collagen.
It surrounds the tumor, dissertation oncology fast track. It is analogous to connective tissue and basal membranewhich is a local condensation, located below normal epithelia. This connective tissue allows oxygen and nutrients to diffuse to the epithelia, which are not vascularized. In the tumor ECM, rapidly, beyond one mm3 of tumor is formed a network of blood vessels, the "neovascularization" induced by " neoangiogenesis " around the tumor and which will allow the diffusion of oxygen and nutrients in the cancer tissue itself, which is not vascularized.
It's a multi-year process. The appearance of cancer is signified by the crossing of the basement membrane to the underlying connective tissue by one or more cancer cells. Several teams, in the USA in particular, had maintained an expertise in the study of non-biological signals in oncology Donald Ingber, Mina Bissell then Valerie Weaver, Rakesh J Jain among others.
But the absolute dominance of genetics and molecular biology since the middle of the 20th century had marginalized this approach until its revival at the beginning of the 21st century. This renewal takes into account the immense gains of genetics and molecular biology in the mechanobiological approach. On the other hand, the PO validates results thanks to these achievements but does not use the concepts. The use of mechanical signals is therefore also the support of mechanobiology whose objective is very different from the PO.
Indeed, as shown in the table above, the study of mechanotransductionwhich is the support of mechanobiology, uses a mechanical "input" signal input but the signal collected at the output the "output" is biological.
As a result, many of the articles published in mechanobiology end with the phrase "we have defined a target to find a therapeutic molecule", which precludes any therapeutic approach by the mechanical signals themselves. But this shift from the physical sciences to the biological sciences is problematic, in the absence of any bridge between these two sciences, one quantitative, physics based on mathematical language and the other qualitative, based on the laws of genetics and molecular biology.
OP aims to study the effect of a mechanical input on a mechanical output. We will see that this output can be dissertation oncology fast track in tissue architecture.
The diagnosis of cancer is made by looking under the microscope a fragment of the tumor biopsy. The tissue phenotype - here cancerous tissue - is the sum of the cellular and tissue phenotype, dissertation oncology fast track.
The phenotype of the cell is dissertation oncology fast track to be the dissertation oncology fast track of the genotype and of the environment: epigenetics expressed in a given cell: thus, a liver cell does not look like a pancreas cell at all because it does not express the same genes yet all present in the genome of all cells.
These characteristics are summarized by: differentiation, cell division mitosisapoptosis or "cell suicide" and cell death. The doctor in charge of the diagnosis under the microscope the pathologist will describe the biopsy based on these criteria. The tissue phenotype is centered on architecture: the normal tissue is Euclidian hexagons, trapezes, circles familiar to our brains; the cancerous is fractal, less familiar.
It can be summed up in a coefficient of fractality very strongly correlated with the prognosis and the components of the cellular phenotype. Thus, a high coefficient of fractality is correlated with a poorly differentiated tumor, with many mitoses, little apoptosis and a poor prognosis.
And here we have to mention Mina Bissell: "in oncology the tissue phenotype is dominant over the cellular genotype". OP was made possible by apparently minor technical changes that allowed in vitro and then in vivo models to be closer to the reality of the cancerous tumor in the patient. For a very long time, two-dimensional 2D cell cultures have been used in glass and then plastic boxes.
The cultured cells thus adhered to the bottom, in very rigid material, rigidity measured by the Young's modulus, very high for these supports. It is expressed in Pascal Paunit of pressure. Then appeared the three-dimensional 3D cultures with cells which constituted multicellular spheres by dividing and were surrounded by a gel-like culture medium at the Dissertation oncology fast track modulus close to those of the living and variable tissues, for example depending on the amount of collagen surrounding these cultures in 3D.
Organoidsspheroids are variants of this type of culture. At the same time the animal models evolved there also towards more similarity with the clinical reality. The human tumor xenograft is today the standard and the orthotopic transplant - for example human cancer of the pancreas in the mouse pancreas - is one of the best experimental models.
The link between the dissertation oncology fast track and the experiment becomes more realistic since these 3D cultures make it possible to use the culture medium surrounding the growing tumor tissue as a "virtual ECM", which can be varied, for example, to increase the pressure around the tumor grown. Similarly, xenograft can constitute a cancer organ with both tissues even if the ECM is of animal origin, dissertation oncology fast track.
It's the ECM. So, when a doctor or a patient feels "a hard lump in the breast" and it is a cancer, what is hard is the ECM while the tumor itself is softer than the normal breast tissue.
This has been demonstrated in vitro and more recently ex vivo and will soon be in vivo. The role of stress on the growth of a spheroid in vitro had already been shown G Helminger already citedbut the experiment of Matthew Paszek last signatory of the article: Valerie Weaver in will give a new dimension to this use of mechanical signals in vitro by showing the passage from a normal architecture of a breast acinus - the elementary unit of the mammary gland - to a cancerous architecture under the influence of a single variable, mechanical, here the surface tension caused by an increasing concentration of collagen in the culture medium surrounding the tumor.
We clearly see the transition from one architecture to another, progressive and reversible if the constraint is relaxed. Changes in the concentration of biological markers of cancerization cateninsintegrinsetc. In addition, this experiment opens the way to the reversibility of cancer, the royal way of treatment, which is intended to replace conventional destructive approaches.
Malignant breast cells cultured in vitro in 3D form a "disorganized" mass translate fractal on the left in the photo. Other authors have extended this work on different models with different mechanical dissertation oncology fast track. F Montel et al, dissertation oncology fast track.
These 3D cultures have also shown the organization of collagen fibers within the ECM and beyond, allowing remote transmission of mechanical signals and a 'tensor dialogue' between the tumor, ECM and normal environment.
But these experiments have in common to apply physical variables surface tension, osmotic pressure that cannot be used in vivo.
M Plodinec et al. extended this work using breast cancer biopsies kept alive ex vivo and then passed to an Atomic Force Microscope AFM to measure the Young's moduli of the different tissue components of these normal breast biopsies, tumors benign and malignant, dissertation oncology fast track. This team finds the results already widely explored on isolated cells and 2D cultures: the cancerous tissues have a Young's modulus around 0.
The ECM has a module greater than 2 kPa. This difference - the cancerous tissue is softer than its normal counterpart - crosses all oncology, all cancers combined and from the dysplastic cell to the tumor and metastatic cells, dissertation oncology fast track. All measurements, cell and tissue, converge towards the same conclusion: the modulus of the cancerous tissue is inversely correlated with the 'dangerousness' of the cancer: the softer the tumor, the more it is undifferentiated, the more it will give dissertation oncology fast track, the less it will respond to current treatments In OP dissertation oncology fast track therapeutic purposes, we find only the dissertation oncology fast track by R Brossel et al.
It is validated in this Proof of Concept. There is a significant difference between the treated group and the control groups. This field imposed on the ECM is superimposed on that already present in the tumor tissue. Note the difference with in vitro: there is no confinement by the ECM in vitro or anchoring by the integrins which ensure the physical continuity between the ECM and the tumor tissue and thus allow the propagation to distance of mechanical signals.
This stress is exerted via ferric nanoparticles, dissertation oncology fast track, therefore magnetizable, located around the tumor and not in the tumor and subjected from outside the animal to a magnetic field gradient generated by fixed magnets. To this work we can link the European project "Imaging Force of Cancer" which as its name indicates aims to measure, voxel by voxel, the constraints involved within the tumoral tissue, dissertation oncology fast track.
This program focuses on the breast, dissertation oncology fast track, the primitive liver and the brain, dissertation oncology fast track. This project is based on MRI elastography, which is the reference method for in vivo, in situ and non-perturbative measurement of the strain, that is to say the very small elastic strain caused in the tissue will give access to the measure of "stress" that is to say of the constraint.
It should therefore make it possible to construct the stress tensor of the tumor tissue in vivo, in situ, without significant disturbance intra-tumoral, obligatory starting base to hope to modify it.
There is also an in vivo experiment which demonstrates the increase of the signals coming from the integrins, induced by the increase of the rigidity of the matrix [26]. The cellular patterning allowed to show the dependence of the cellular architecture on the tensions generated by the support, variable according to the rigidity of these supports.
This made it possible to hypothesize about the transmission of mechanical signals between the "outside", here the support glass dissertation oncology fast track plastic then geland the CytoSKeleton CSK and the nucleus. The equilibrium, in the CSK of each cell, is between contractile microfilaments and microtubules resistant to compression; it is also done in the membership of the ECM by a game of pressure and tension that cancel out in a situation of equilibrium.
Energy is given by actin. Increased stiffness of the ECM: the spreading of the cell - on the support, representation of the ECM dissertation oncology fast track is necessary for the cell division thus the growth. Decrease of the rigidity of the ECM: when the ECM is deformed, the cell traction causes the stop of the growth and a differentiation of the cell or an apoptosis. The soft material that transmits the mechanical signals is therefore pre-stressed and this allows the transmission of forces in the body with a quantitative distribution according to dissertation oncology fast track scale: the skeleton, a macroscopic structure, dissertation oncology fast track transmit much greater forces than an isolated organ.
also support the production of energy. Indeed, mitochondria are an integral part of this network and semi-solid non-liquid phase biochemistry is an important part of tissue metabolism. Here we find a principle of treatment by the mechanical dissertation oncology fast track. Circulating Tumor Cells CTCs are isolable and their rigidity can be measured quite easily.
Numerous articles have been able to verify what was already known for cells in 2D culture: the Young's modulus of CTC is very strongly correlated with the severity of cancer in all its parameters: differentiation, metastatic potential, prognostic and predictive correlation And these correlations are valid for metaplastic, dysplastic, in situ and cancerous cells.
These CTCs must first cross the ECM, enter the bloodstream or lymphatic vessels, and then leave the circulation to attach to a tissue for metastasis. Many articles have recently commented on this "journey" and the many physical elements that punctuate it. The tumor accumulates mechanical energy during its growth. In an article by Stylianopoulos, the author uses a simple technique to highlight tumor constraints: an ex vivo tumor laser cutting frees the accumulated constraints, dissertation oncology fast track.
They are expressed as bulges that can be measured and related to the underlying stress. In the center of the tumor the radial and circumferential stresses are compressive; in the periphery of the tumor the radial stress is compressive, and the circumferential stress is a linear traction along the outer limit of the tumor, dissertation oncology fast track. Tumor growth causes stress on the healthy tissues around it.
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Physical oncology (PO) is defined as the study of the role of mechanical signals in a cancerous tumor. The mechanical signals can be forces, pressures ("pull", "push" and "shear" designating the forces / pressures that push, pull or are tangential). If we generalize we will speak of "stress field" and "stress tensor" Sep 02, · University of Michigan College of Pharmacy Church St. Ann Arbor, MI Patients and Non-Oncology Doctors Struggle to Keep up with the Pace of Change in Oncology, Research Shows 17 Sep Two studies [to be] presented at the ESMO Congress suggest a need for broader education on current standards of cancer care
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