MYC: there is more to it than cancer

MYC; Non-oncological diseases; Transcription factorMYC; Enfermedades no oncológicas; Factor de transcripcionMYC; Malalties no oncològiques; Factor de transcripcióMYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4 decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for "MYC oncogene") have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC's physiological functions become co-opted for tumour initiation and maintenance. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Authors acknowledge funding support from the Spanish Ministry of Science and Innovation (Fondo de Investigación en Salud [FIS] PI19/01277, the State Agency for Research (Agencia Estatal de Investigación) as a Center of Excellence Severo Ochoa (CEX 2020-001024-S/AEI/10.13039/501100011033), the Generalitat de Catalunya (AGAUR 2021/SGR 01509), and the FERO foundation

Regulatory T cells but not NKT I cells are modulated by a single low-dose Cyclophosphamide in a B cell lymphoma tumor-model

Aim: Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low doses leads to an enhancement of the antitumor immune response. Our objective was to study the modulation, if any, by low dose Cy, of T regulatory (Treg) and natural killer T (NKT) I cells, two cell populations of the innate immune response with opposing effects on the tumors, in a rat B cell lymphoma model. Methods: Inbred e rats were challenged s.c. with L-TACB lymphoma and on day 14 animals were distributed in two groups. Treated: injected i.p. with cyclophosphamide (10mg/kg of body weight) and Control: injected i.p. with saline. Blood samples were taken from days 0 to 21 and the percentage of T regulatory and natural killer T I cells were determined by flow cytometry. Results: We found that the increase of natural and inducible T regulatory cells of peripheral blood achieved during tumor growth was significantly downregulated by cyclophosphamide. On the contrary, natural killer T I cells were not modulated by the treatment. Conclusion: The antimetastatic effect of a single low dose of Cy would be due, at least in part, to downregulation of natural and inducible T regulatory cells

Effect of p95HER2/611CTF on the Response to Trastuzumab and Chemotherapy

Human epidermal growth factor receptor 2 (HER2)–positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906mm3, 95% confidence interval = 1274 to 538 mm3; trastuzumab+doxorubicin: 259mm3, 95% confidence interval = 387 to 131 mm3; P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells

Biomarkers to identify and isolate senescent cells

This paper was accepted for publication in the journal Ageing Research Reviews and the definitive published version is available at http://dx.doi.org/10.1016/j.arr.2016.05.003.Aging is the main risk factor for many degenerative diseases and declining health. Senescent cells are part of the underlying mechanism for time-dependent tissue dysfunction. These cells can negatively affect neighbouring cells through an altered secretory phenotype: the senescence-associated secretory phenotype (SASP). The SASP induces senescence in healthy cells, promotes tumour formation and progression, and contributes to other age-related diseases such as atherosclerosis, immune-senescence and neurodegeneration. Removal of senescent cells was recently demonstrated to delay age-related degeneration and extend lifespan. To better understand cell aging and to reap the benefits of senescent cell removal, it is necessary to have a reliable biomarker to identify these cells. Following an introduction to cellular senescence, we discuss several classes of biomarkers in the context of their utility in identifying and/or removing senescent cells from tissues. Although senescence can be induced by a variety of stimuli, senescent cells share some characteristics that enable their identification both in vitro and in vivo. Nevertheless, it may prove difficult to identify a single biomarker capable of distinguishing senescence in all cell types. Therefore, this will not be a comprehensive review of all senescence biomarkers but rather an outlook on technologies and markers that are most suitable to identify and isolate senescent cells

Is C-reactive protein/albumin ratio of advanced-stage non-small cell lung cancer patients able to predict mortality in the admission for palliative care?

WOS:000570243000018PubMed: 33311881Context: Lung cancer is frequent and mortal cancer. The predicting mortality may be helpful for cancer management. Aim: The purpose of the study was to evaluate the role of baseline C-reactive protein (CRP)/albumin ratio (CAR) in relation to hospital mortality, the setting of advanced stage non-small cell lung cancer (NSCLC). Materials and Methods: The present study is a retrospective analysis and included 77 adult patients with Stage IV NSCLC who were hospitalized for supportive care. All patients are divided into two groups as survivors and nonsurvivors. CAR on the admission was compared between groups. The correlation between CAR and the death time was investigated. The cutoff level of CAR was calculated, and patients with a high level were described in two groups. Results: For all participants, the mean age was 63.0 +/- 9.9 years, and the median values of CRP and albumin levels were 15.3 mg/dl (1-51.5) and 5.7 g/dl (0.02-22.7), respectively. CAR was significantly lower in the survivor group. By receiver operation curve analysis, the cutoff levels of CRP and CAR were determined as 10.8 and 3.5, respectively. The odds ratio of mortality was 3.85 (1.49-9.94 95% confidence interval [CI], P = 0.006) for higher than cutoff levels of CAR. The odds ratio was 3.38 (1.32-8.65 95% CI, P = 0.01) for higher CRP levels. There was a significant but weak negative correlation between the time of death and both CRP and CAR in the nonsurvivor group (r = -0.46, P = 0.002; r = -0.48, P = 0.001, respectively). Conclusion: The present study showed that CAR was significantly increased in nonsurvivors. CAR may be a cheap, easy, and effective tool for predicting the death and its time of hospitalized NSCLC patients

Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies

<div><p>A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies.</p></div

Effect of p95HER2/611CTF on the Response to Trastuzumab and Chemotherapy

Human epidermal growth factor receptor 2 (HER2)–positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259mm(3), 95% confidence interval = 387 to 131 mm(3); P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells