The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer cell phenotype and resistance to therapy.

This Perspective addresses the interactions of cancer stem cells (CSC) with environment which result in the modulation of CSC metabolism, and thereby of CSC phenotype and resistance to therapy. We considered first as a model disease chronic myeloid leukemia (CML), which is triggered by a well-identified oncogenetic protein (BCR/Abl) and brilliantly treated with tyrosine kinase inhibitors (TKi). However, TKi are extremely effective in inducing remission of disease, but unable, in most cases, to prevent relapse. We demonstrated that the interference with cell metabolism (oxygen/glucose shortage) enriches cells exhibiting the leukemia stem cell (LSC) phenotype and, at the same time, suppresses BCR/Abl protein expression. These LSC are therefore refractory to the TKi Imatinib-mesylate, pointing to cell metabolism as an important factor controlling the onset of TKi-resistant minimal residual disease (MRD) of CML and the related relapse. Studies of solid neoplasias brought another player into the control of MRD, low tissue pH, which often parallels cancer growth and progression. Thus, a 3-party scenario emerged for the regulation of CSC/LSC maintenance, MRD induction and disease relapse: the “hypoxic” versus the “ischemic” vs. the “acidic” environment. As these environments are unlikely constrained within rigid borders, we named this model the “metabolically-modulated stem cell niche.

Experimental assessment of inter-centre variation in stopping-power and range prediction in particle therapy

Purpose: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network. Material and methods: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer. Results: An inter-centre variation in SPR prediction (2 sigma) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2 sigma) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung-and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average. Conclusion: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion. (C) 2021 The Authors. Published by Elsevier B.V

Chronic myeloid leukemia and hepatoblastoma: Two cancer models to link metabolism to stem cells

Low oxygen tension is a critical aspect of the stem cell niche where stem cells are long-term maintained. In physiologically hypoxic stem cell niches, low oxygen tension restrains the clonal expansion of stem cells without blocking their cycling, thereby contributing substantially to favour their self-renewal. The capacity of stem cells, haematopoietic stem cells in particular, to reside in low oxygen is likely due to their specific metabolic profile. A strong drive to the characterization of this profile emerges from the notion that cancer stem cells (CSC), like normal stem cells, most likely rely on metabolic cues for the balance between self-renewal/maintenance and clonal expansion/differentiation. Accordingly, CSC homing to low oxygen stem cell niches is the best candidate mechanism to sustain the so-called minimal residual disease. Thus, the metabolic profile of CSC impacts long-term cancer response to therapy. On that basis, strategies to target CSC are intensely sought as a means to eradicate neoplastic diseases. Our metabolic approach to this challenge was based on two different experimental models: A) the Yoshida’s ascites hepatoma AH130 cells, a highly homogeneous cancer cell population expressing stem cell features, used to identify, in CSC adapted to oxygen and/or nutrient shortage, metabolic features of potential therapeutic interest; B) chronic myeloid leukaemia, used to evaluate the impact of oxygen and/or nutrient shortage on the expression of an oncogenetic protein, the loss of which determines the refractoriness of CSC to oncogene-targeting therapies

One more stem cell niche: how the sensitivity of chronic myeloid leukemia cells to imatinib mesylate is modulated within a “hypoxic” environment

This is a review (by no means comprehensive) of how the stem cell niche evolved from an abstract concept to a complex system, implemented with a number of experimental data at the cellular and molecular levels, including metabolic cues, on which we focused in particular. The concept was introduced in 1978 to model bone marrow sites suited to host hematopoietic stem cells (HSCs) and favor their self-renewal, while restraining clonal expansion and commitment to differentiation. Studies of the effects of low oxygen tension on HSC maintenance in vitro led us to hypothesize niches were located within bone marrow areas where oxygen tension is lower than elsewhere. We named these areas hypoxic stem cell niches, although a low oxygen tension is to be considered physiological for the environment where HSCs are maintained. HSCs were later shown to have the option of cycling in low oxygen, which steers this cycling to the maintenance of stem cell potential. Cell subsets capable of withstanding incubation in very low oxygen were also detected within leukemia cell populations, including chronic myeloid leukemia (CML). The oncogenetic Bcr/Abl protein is completely suppressed in these subsets, whereas Bcr/Abl messenger ribonucleic acid is not, indicating that CML cells resistant to low oxygen are independent of Bcr/Abl for persistence in culture but remain genetically leukemic. Accordingly, leukemia stem cells of CML selected in low oxygen are refractory to the Bcr/Abl inhibitor imatinib mesylate. Bcr/Abl protein suppression turned out to be actually determined when glucose shortage complicated the effects of low oxygen, indicating that ischemia-like conditions are the driving force of leukemia stem cell refractoriness to imatinib mesylate. These studies pointed to “ischemic” stem cell niches as a novel scenario for the maintenance of minimal residual disease of CML. A possible functional relationship of the “ischemic” with the “hypoxic” stem cell niche is discussed

Plug’n’play proton radiography with commercial QA equipment - A first hand practical how-to

International audienceProton imaging has long been proposed as alternative or complementary imaging modality in ion beam therapy offering a direct probe of the relative stopping power. However, it is yet to see an integration into the clinical workflow. Several groups around the world are working on the technical implementation of proton radiography/tomography set-ups based on more or less complex hardware designs. Many of these set-ups come along with prerequisites for the treatment facility: coupling with trigger output from the accelerator, unusually low particle fluence, additional integration of dedicated hardware. Furthermore, many set-ups rely on non-certified prototype hardware components. These factors limit the immediate accessibility of proton imaging in ion beam therapy facilities. In this contribution, we will report about a recent series of experiments conducted at the Institut Curie - Proton Therapy Center in Orsay, France. We acquired proton radiographies of various phantoms, using a commercial range telescope available in the facility. The detector was operated in free running mode and standard beam parameters were used, rendering the set-up plug’n’play. We will further elucidate the dedicated data and image processing involved to produce proton radiographies from the raw data and illustrate the good image quality which can be reached even with such a comparatively simple set-up. The purpose of this contribution is to share a first hand practical how-to and to encourage the idea that proton radiographic imaging can be realized with reasonable effort employing hardware already available in ion beam therapy facilities for quality assurance and/or positioning applications

High WET resolution proton radiography using dedicated image processing methods and a commercial plug'n'play detector

International audienceProton transmission imaging uses protons with high enough energy to fully traverse the phantom/patient and to be captured in a suitable detector placed behind it. The measured residual energy or residual range provide a direct estimate of the water equivalent thickness (WET) of the image volume. Requirements for proton imaging to be exploitable in clinical practice include: (a) sufficient WET accuracy and (b) integrability into the treatment room and the clinical workflow. In this work, we report on experiments performed at the Institut Curie - Proton therapy center in Orsay (IC-CPO), France, using a commercial range telescope commonly employed for quality assurance measurements. The purpose was to keep the experimental aspects as simple as possible and to achieve nonetheless high WET resolution radiographies by developing and applying dedicated image processing methods. We explain these methods in detail and discuss their performance. We assess theWET accuracy based on two different reference phantoms: a CIRS electron density phantom with tissue equivalent inserts and a homogeneous step phantom. We nd an agreement between the measured and the ground truth WET values of better than 0.5mm and 0.2mm, respectively. Our work suggests that proton radiographies with good WET accuracy can be obtained with a reasonable experimental effort that would facilitate integration into clinical routine

High Resolution Proton Radiography Using Sophisticated Image Processing Methods and a Commercial Plug and Play Detector

International audienceWe measured proton radiographies employing commercial plug and play detectors and developed sophisticated data and image processing methods to increase the water equivalent thickness (WET)accuracy of proton radiographies