Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer?

Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers.KEY WORDS: Acute myeloid leukaemia, Cancer, Clonal evolution, In vivo models of leukaemia, Mutation     

Intraoperative radiation therapy as part of breast conserving therapy of early breast cancer—Results of one-year follow-up

Aim

The aim of this study was to assess the therapeutic effect of intraoperative radiotherapy, describe the method, and examine the occurrence of side effects and quality of life.

Background

Breast conserving therapy has recently become a standard treatment modality in patients with early invasive cancer. Radiotherapy, along with surgery, is an integral part of such treatment. The important thing of radiotherapy is to deliver a high dose to the tumour bed. One of the methods is the intraoperative radiotherapy.

Materials and methods

The analysis comprised sixty Tis-T2N0-1A breast cancer patients treated with breast conserving surgery. Patients’ mean age was 57 years (range: 32–73 years). Intraoperative radiation therapy was delivered in the operating theatre during surgery and involved a single dose of 10 Gy with an electron beam of 4, 6, 9 or 12 MeV. After that, all patients were treated with whole breast irradiation. During one year observation photos and side effects examination were made.

Results

Physical and imaging examinations performed during a one-year follow-up revealed no local or distant relapse and good tolerance of IORT. Acute mild responses to the radiotherapy occurred in 23.3% of patients. Based on the examination, a good and very good cosmetic effect was found in 78.3%, with 83.3% of patients evaluating their treatment effects in the same way.

Conclusions

Due to its exceptional physical and radiobiological properties, intraoperative radiation therapy can be a good alternative to other methods of boosting dose to the post-operative site in management of low stage breast cancer, enabling a precise therapy to the tumour bed.     

Using the “reverse Warburg effect” to identify high-risk breast cancer patients

We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the “Reverse Warburg Effect,” as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly assess the prognostic value of the “Reverse Warburg Effect.” MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (< 18% survival at 10 y post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-y survival rates of ~97% (p-value < 10^?32). High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 10^?14), a known marker of early tumor recurrence and metastasis. In fact, the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the “conventional” Warburg effect does not predict clinical outcome. Thus, the “Reverse Warburg Effect” or “parasitic” energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such as, AR-C155858, AR-C117977, and AZD-3965).     

Golgi’s way: a long path toward the new paradigm of the intra-Golgi transport

The transport of proteins and lipids is one of the main cellular functions. The vesicular model, compartment (or cisterna) maturation model, and the diffusion model compete with each other for the right to be the paradigm within the field of the intra-Golgi transport. These models have significant difficulties explaining the existing experimental data. Recently, we proposed the kiss-and-run (KAR) model of intra-Golgi transport (Mironov and Beznoussenko in Int J Mol Sci 13(6):6800–6819, 2012), which can be symmetric, when fusion and fission occur in the same location, and asymmetric, when fusion and fission take place at different sites. Here, we compare the ability of main models of the intra-Golgi transport to explain the existing results examining the evidence in favor and against each model. We propose that the KAR model has the highest potential for the explanation of the majority of experimental observations existing within the field of intracellular transport.     

The somatic mutation theory of cancer: growing problems with the paradigm?

The somatic mutation theory has been the prevailing paradigm in cancer research for the last 50 years. Its premises are: (1) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations, (2) the default state of cell proliferation in metazoa is quiescence, and (3) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. From this compelling simplicity, an increasingly complicated picture has emerged as more than 100 oncogenes and 30 tumor suppressor genes have been identified. To accommodate this complexity, additional ad hoc explanations have been postulated. After a critical review of the data gathered from this perspective, an alternative research program has been proposed. It is based on the tissue organization field theory, the premises of which are that carcinogenesis represents a problem of tissue organization, comparable to organogenesis, and that proliferation is the default state of all cells. The merits of these competing theories are evaluated herein.     

A century of research into the cause of cancer: is the new oncogene paradigm revolutionary?

Contemporary oncological research is predominantly characterised by genetic explanations, a situation which may be briefly denoted as the oncogene paradigm. This essay discusses why the new paradigm was perceived so attractive that it could take over the whole field of oncology within a time-span of less than two decades. It is argued that the revolutionary character of the oncogene paradigm stems from the fact that it transcends a dichotomy which has kept experimental cancer research divided for more than three quarters of a century. This concerns the dichotomy between so-called exogenous and endogenous explanations of cancer causation. This essay mainly focuses on the role of the exogenous/endogenous dichotomy in the reception of research on oncogenic viruses, especially discussing the work of Nobel laureate Peyton Rous on cancer viruses at the Rockefeller Institute. Rous was severely criticised by James Ewing, director of the Memorial Hospital for Cancer and Allied Diseases in New York, who held the idea that the origin of cancer was based in the cell. The twentieth century controversy over oncogenic viruses is placed in the context of the intense discussion over causality in medicine during the first decades of the twentieth century in Germany. It is argued that the oncogene paradigm may be seen as revolutionary because it succeeded in uniting the exogenous and endogenous explanations of cancer in a single paradigm.     

Successful pregnancy after breast cancer therapy: dream or reality?

Background

Nowadays, more breast cancer patients want to have children after the diagnosis of cancer. The purpose of this study is to review the possibility and risks of giving birth among women with breast cancer previously treated by chemotherapy.

Case presentation

Two young women aged 28 and 34 respectively, were treated in our clinic for breast cancer, the first (negative hormonal receptors) by surgery, chemotherapy and radiotherapy and the second (positive hormonal receptors) by surgery, radiotherapy and tamoxifen. They both became pregnant, 1 and 8 years after completion of the therapy respectively.

Results

Laboratory testing during pregnancy was negative in both cases and after an uneventful course each woman gave birth to a perfectly healthy child. The first patient breastfed her baby for three months, while the second one did not breastfeed her baby at all.

Conclusion

Women undergoing chemotherapy for breast cancer can maintain their fertility and get pregnant. Previous chemotherapy for breast cancer does not present any supplementary risks for the child's mental or physical health.

     

Identification of novel SNPs in SYK gene of breast cancer patients: computational analysis of SNPs in the 5′UTR

Spleen tyrosine kinase (SYK) is a non receptor type tyrosine kinase and a known candidate tumor suppressor gene in breast carcinoma. Loss of Syk is associated with breast cancer invasion and increased cell mortality. The main goal of our study was to detect germ-line polymorphisms in SYK gene in breast cancer affected females of Pakistani origin, in order to understand the genetic basis of complex human breast cancer. Seven novel SYK gene SNPs were identified in breast cancer patients. Among these, three were identified in intronic region, one at the 5'splice donor site (5'SD) and three in 5'untranslated region (5'UTR) of SYK gene. Mutations at the 5'SD and at 5'UTR can be crucial and could be responsible for generation of mutated Syk protein. In silico analysis of the 5'UTR variations revealed that one of the mutations was responsible for generation of a more stable structure of 5'UTR. Such a change in pre-mRNA could potentially down regulate SYK expression. These findings add to the growing literature implicating dysfunctional SYK gene as a contributor to human breast cancer, and suggest that therapies targeting its molecular pathways could provide effective means of treating/preventing breast cancer.     

Lactosylceramide synthase β-1,4-GalT-V: A novel target for the diagnosis and therapy of human colorectal cancer

Little is known about an oncogenic signal transducer β-1,4-galactosyltransferase-V (β-1,4-GalT-V), in human colorectal cancer. Using quantitative RT-PCR, immunohistochemical staining and ELISA assays, we determined that β-1,4-GalT-V gene/protein expression is specifically increased in human colorectal cancer (CRC) tumors, compared to visibly normal tissue. Furthermore, we observed a marked increase in its enzymatic activity, and its product lactosylceramide. Moreover, we found increased dihydrosphingolipid metabolites, in particular dihydrosphingomyelin in cancer tissue compared to normal. Further, inhibition of glycosphingolipid synthesis by the synthetic ceramide analog, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), concurrently inhibited colorectal cancer cell (HCT-116) proliferation, as well as β-1,4-GalT-V mass and several glycosphingolipid levels. We conclude that β-1,4-GalT-V may serve as a diagnostic and therapeutic biomarker for the progression of human colorectal cancer, and consequently, inhibition of GSL synthesis may be a novel approach for the treatment of this life-threatening disease.     

Dynamic theory of action-perception patterns: the “moving room” paradigm

Action-perception patterns are studied theoretically in terms of equations of motion that capture the coordination capacity of the nervous system. We consider intrinsic dynamics in the absence of visual information that contain a single posture state as a fixed point attractor. We couple these intrinsic dynamics to visual information that stabilizes posture in the visual world. This leads to a theory of postural sway induced by an optic flow field (moving room paradigm). The optic flow is parametrized in a simplest approximation by the expansion rate of a relevant perceptual target. We show how temporal stability as the key concept of this theory can lead to prediction and serve as a measure of perceptual coupling. Finally, we discuss the relation of the present theory to biological cybernetics.     

Therapeutic effects of metformin in breast cancer: involvement of the immune system?

Breast cancer and associated diabetes mellitus have gained raising interest as an elevated risk of breast cancer prognosis resulting in increased mortality in diabetic patients. In this context, the long-acting insulin analog glargine and other antidiabetics have been discussed to promote tumorigenesis. In contrast, the biguanide class oral antidiabetic metformin has been shown capable of enhancing cell cycle arrest and inducing apoptosis as well as reducing growth factor signaling. Consequently, several studies are underway to evaluate a possible role of metformin in breast cancer treatment. Although mechanisms involved are not definitely clear yet, here, we discuss metformin’s anticancer effects including the potential impact of the immune system.     

Characterisation of disseminated tumor cells in the bone marrow of breast cancer patients by the Thomsen–Friedenreich tumor antigen

The detection of disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients has proved prognostic significance in all stages of the disease. Further characterisation of those cells could help to improve the biological understanding of metastases, develop targeted therapies and define surface markers for enrichment techniques. The Thomsen–Friedenreich (TF) antigen has been shown to be a tumor specific antigen in breast cancer. The aim of this study was to investigate the expression of TF on DTC-BM in 25 patients. Bone marrow samples were first double-stained by a Cy3 conjugated cytokeratin (CK) antibody (ab) A45 B/B3 (IgG) and anti-TF ab Nemod 2 (IgM), followed by Cy2 conjugated goat anti-mouse IgM ab. For further characterisation samples were also double-stained with anti-TF ab Nemod 2 (IgM), followed by Cy2 conjugated goat anti-mouse IgM ab, and anti MUC1 ab A76-A/C7 IgG, followed by Cy3 conjugated goat anti-mouse IgG. CK positive DTC-BM showed co-expression of TF antigen in 22/23 patients (96%) and 61 of 62 detected cells (98%). Mononuclear BM cells without CK expression were also negative for TF. All of the TF positive cells showed strong MUC1 expression. This is the first study showing co-expression of CK and TF as markers of DTC-BM. Double staining experiments of TF and MUC1 expression showed that MUC1 is the carrier protein of TF in these cells. As TF is a specific marker of DTC-BM, it could be used as a target for antibody based therapy and immunomagnetic enrichment techniques for the isolation of DTC-BM.     

Chronological age or biological age: What drives the choice of adjuvant treatment in elderly breast cancer patients?

Ma and colleagues reported in their study on 12,004 elderly patients published on Breast J. 2020, that adjuvant chemotherapy was not associated with overall survival. Given the toxicities associated with systemic treatments, caution recommendation or omission of chemotherapy may be considered in elderly patient selection especially when comorbidities are present. We agree with authors final conclusions but we want to highlight that to define the adjuvant therapy in BC elderly patients several factors need to be taken into account. One of the main issues is the lack of universal and unique guidelines to define elderly patients. In clinical practice it can be very difficult to estimate the benefit/risk ratio in elderly patients because chemotherapy-induced toxicity is worse than in younger individuals. For these reasons, beyond comorbidities, the choice of adjuvant therapy for elderly patients must also be based both on chronological and biological age. Moreover, the multidisciplinary team for the elderly patient evaluation should include both the geriatrician and the molecular biologist.     

Should the management of radiation therapy for breast cancer be standardized? Results of a survey on current French practices in breast radiotherapy

BackgroundBreast cancer is the most frequent cancer in women in France. Its management has evolved considerably in recent years with a focus on reducing iatrogenic toxicity. The radiotherapy indications are validated in multidisciplinary consultation meetings; however, questions remain outstanding, particularly regarding hypofractionated radiotherapy, partial breast irradiation, and irradiation of the internal mammary chain and axillary lymph node area.Materials and methodsAn online survey was sent to 47 heads of radiotherapy departments in France. The survey consisted of 22 questions concerning indications for irradiation of the supraclavicular, internal mammary and axillary lymph node areas; irradiation techniques and modalities; prescribed doses; and fractionation.ResultsTwenty-four out of 47 centers responded (response rate of 51%). This survey demonstrated a wide variation in the prescribed dose regimen, monoisocentric radiotherapy, and indications of irradiation of the lymph node areas.ConclusionThis survey provides insight into the current radiotherapy practice for breast cancer in France. It shows the need to standardize practices.     

Using the “reverse Warburg effect” to identify high-risk breast cancer patients: Stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers

We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H₂O₂), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the “reverse Warburg effect,” as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immunostaining of human breast cancer tissue microarrays (TMAs; >180 triple-negative patients) to directly assess the prognostic value of the “reverse Warburg effect.” MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (<18% survival at 10 years post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-year survival rates of ∼97% (p-value < 10⁻³²). High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 10⁻¹⁴), a known marker of early tumor recurrence and metastasis. In fact, the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the “conventional” Warburg effect does not predict clinical outcome. Thus, the “reverse Warburg effect” or “parasitic” energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such as, AR-C155858, AR-C117977 and AZD-3965).Key words: caveolin-1, oxidative stress, pseudohypoxia, lactate shuttle, MCT4, metabolic coupling, tumor stroma, predictive biomarker, SLC16A3, monocarboxylic acid transporter, two-compartment tumor metabolism     

Personalized liposome–protein corona in the blood of breast,gastric and pancreatic cancer patients

When nanoparticles (NPs) are dispersed in a biofluid, they are covered by a protein corona the composition of which strongly depends on the protein source. Recent studies demonstrated that the type of disease has a crucial role in the protein composition of the NP corona with relevant implications on personalized medicine. Proteomic variations frequently occur in cancer with the consequence that the bio-identity of NPs in the blood of cancer patients may differ from that acquired after administration to healthy volunteers. In this study we investigated the correlation between alterations of plasma proteins in breast, gastric and pancreatic cancer and the biological identity of clinically approved AmBisome-like liposomes as determined by a combination of dynamic light scattering, zeta potential analysis, one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) and semi-quantitative densitometry. While size of liposome–protein complexes was not significantly different between cancer groups, the hard corona from pancreatic cancer patients was significantly less negatively charged. Of note, the hard corona from pancreatic cancer patients was more enriched than those of other cancer types this enrichment being most likely due to IgA and IgG with possible correlations with the autoantibodies productions in cancer. Given the strict relationship between tumor antigen-specific autoantibodies and early cancer detection, our results could be the basis for the development of novel nanoparticle-corona-based screening tests of cancer.