O maior crescimento do câncer é à noite: sob a regência do cortisol
É no estresse do jejum da madrugada, com cortisol e outras moléculas do estresse mais altas, que o câncer se espalha e cresce
[Este artigo já foi publicado no nosso antigo blog do substack ao qual, recentemente,me foi vetado o acesso para postar novas publicações. Dessa forma e para que possa ser conhecido pelos leitores deste novo blog -intitulado outramedicina2024.substack.com - , faço aqui a republicação do artigo]
O trabalho científico foi publicado em Nature Communications e resenhado abaixo [A][C].
Nele, os cientistas mostram que o câncer cresce mais velozmente à noite, sob o regime do cortisol. Adrenalina sendo parte fundamental desse processo, bom lembrar [e publicamos nota neste blog sobre adrenalina e câncer].
O que os achados experimentais sugerem, é que são os picos e quedas do cortisol no curso de 24 horas que promovem ou inibem o crescimento do câncer.
Esta vem sendo a linha de pensamento de R. Peat de longa data sobre a gênese tumoral, invariavelmente destacando o papel do estresse e seus hormônios. Da mesma forma - como lembra G Dinkov - R. Peat propunha, dentre outras coisas de mais peso [como progesterona, AAS], o uso de pó da casca da planta cáscara sagrada em tumores, por conta de sua propriedade de suprimir a síntese do cortisol, o que explicaria boa parte dos seus efeitos anticâncer [B].
À noite, justamente, o cortisol alcança seus níveis mais altos, amanhecendo em níveis elevados ao despertar, .
O cortisol é mais alto naquele período entre as 5 e 8 da manhã [AM]. É o período, no qual, grande parte das pessoas enfermas nos hospitais vão a óbito [B].
Dinkov também registra a opinião de R. Peat, de que “alguns praticantes do Tai-Chi – da medicina chinesa tradicional – provavelmente têm ciência disso e essa seria a razão pela qual eles acordam muito cedo, fazem seus exercícios calmantes e então voltam de novo para a cama por mais algumas horas [até às 8 a 10 da manhã, AM].
No entanto, simplesmente acordar em torno das 5 h e consumir um pouco de leite com açúcar pode ser suficiente para restringir o estresse” [B].
O estudo abaixo [A][C] confirma aquele fenômeno de que naquelas horas noturnas – do cortisol mais alto - o câncer ganha velocidade, cresce e se espalha pelo corpo.
Este estudo foi conduzido por Dr M Lauriola, pós-doutor do grupo do Dr Y. Yarden, do Weizmann Institute [de biologia].
Focaram em determinado receptor do cortisol, o EGFR [em inglês], mais ativo durante o sono e silenciado nas horas de vigília.
Deram a ratos com câncer uma droga que inibe aquele receptor do cortisol. E verificaram, depois, que conforme a hora de administração da droga [lapatinib] a cada diferente grupo de animais, que o tumor crescia mais ou menos.
Puderam assim vincular cortisol a crescimento tumoral.
E confirmaram que é a alta nos níveis de cortisol que comanda o crescimento tumoral.
Concluíram que nessas horas seria também o momento de se usar drogas anticâncer. [Foi publicada nota neste blog sobre o suco de laranja doce e seu papel, ao lado da gelatina animal, no combate ao estresse da madrugada].
Em suma, o original do artigo [C] defende que o planejamento do tratamento do câncer precisa respeitar o relógio circadiano, e agir quando o cortisol é mais baixo.
E, logicamente, exige uma estratégia para manter baixos os níveis de cortisol. De estresse.
Também podemos concluir que a relação entre estresse e desenvolvimento tumoral é direta e hormonal. Estresse é hormônio do estresse por excelência e, claramente, impulsos emocionais negativos, cronicamente instalados [ou mesmo em sua forma aguda] no nosso organismo tendem a impulsionar o câncer. Não são mundos separados. Este é um fato mais de uma vez demonstrado pela ciência.
Daqui deriva a importância estratégica do afeto, do acolhimento, do bom status emocional de quem pretenda enfrentar a doença crônico-degenerativa com todas as armas.
G Dantas [Publicado originalmente em Brasília, 17-2-24]
As informações aqui presentes não pretendem servir para uso diagnóstico, prescrição médica, tratamento, prevenção ou mitigação de qualquer doença humana. Não pretendem substituir a consulta ao profissional médico ou servir como recomendação para qualquer plano de tratamento. Trata-se de informações com fins estritamente educativos. Nenhuma das notas aqui presentes, neste blog, conseguirá atingir o contexto específico do paciente singular, nem doses, modo de usar etc. Este trabalho compete ao paciente com seu médico. Isso significa que nenhuma dessas notas - necessariamente parciais - substitui essa relação.
Referências ___________________
[A] WEIZMANN WONDER WANDER, 2014. Tumors Might Grow Faster at Night
06.10.2014 “They emerge at night, while we sleep unaware, growing and spreading out as quickly as they can. And they are deadly. In a surprise finding that was recently published in Nature Communications, Weizmann Institute of Science researchers showed that nighttime is the right time for cancer to grow and spread in the body. Their findings suggest that administering certain treatments in time with the body’s day-night cycle could boost their efficiency.
This finding arose out of an investigation into the relationships between different receptors in the cell – a complex network that we still do not completely understand. The receptors – protein molecules on the cell’s surface or within cells – take in biochemical messages secreted by other cells and pass them on into the cell’s interior. The scientists, led by Dr. Mattia Lauriola, a postdoctoral fellow in the research group of Prof. Yosef Yarden of the Weizmann Institute’s Biological Regulation Department, working together with Prof. Eytan Domany of the Physics of Complex Systems Department, focused on two particular receptors. The first, the epidermal growth factor receptor, EGFR, promotes the growth and migration of cells, including cancer cells. The second binds to a steroid hormone called a glucocorticoid (GC). Glucocorticoids play a role in maintaining the body’s energy levels during the day, as well as the metabolic exchange of materials. It is often called the stress hormone because its levels rise in stressful situations, rapidly bringing the body to a state of full alert.
With multiple receptors, the cell receives all sorts of messages at once, and some of these messages can take precedence over others. In the experiment, Lauriola and Yarden found that cell migration – the activity promoted by the EGF receptor – is suppressed when the GC receptor is bound to its steroid messenger.
Since the steroid levels peak during waking hours and drop off during sleep, the scientists asked how this might affect the second receptor – EGFR. Checking the levels of this activity in mice, they found that there was a significant difference: This receptor is much more active during sleep and quiescent during waking hours.
How relevant are these findings for cancers, particularly those which use the EGF receptors to grow and spread? To find out, the scientists gave Lapatinib – one of the new generation of cancer drugs – to mouse models of cancer. This drug, used to treat breast cancer, is designed to inhibit EGFR, and thus to prevent the growth and migration of the cancer cells. In the experiment, they gave the mice the drug at different times of day. The results revealed significant differences between the sizes of tumors in the different groups of mice, depending on whether they had been given the drug during sleep or waking hours. The experimental findings suggest that it is indeed the rise and fall in the levels of the GC steroids over the course of 24 hours that hinder or enable the growth of the cancer.
The conclusion, say the scientists, is that it could be more efficient to administer certain anticancer drugs at night.
“It seems to be an issue of timing,” says Yarden. “Cancer treatments are often administered in the daytime, just when the patient’s body is suppressing the spread of the cancer on its own. What we propose is not a new treatment, but rather a new treatment schedule for some of the current drugs.”
Prof. Eytan Domany's research is supported by the Leir Charitable Foundations; Mordechai Segal, Israel; and the Louis and Fannie Tolz Collaborative Research Project. Prof. Domany is the incumbent of the Henry J. Leir Professorial Chair.
Prof. Yosef Yarden’s research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Maurice and Vivienne Wohl Biology Endowment; the Louis and Fannie Tolz Collaborative Research Project; the European Research Council; and the Marvin Tanner Laboratory for Research on Cancer. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.
Disponível em: https://wis-wander.weizmann.ac.il/life-sciences/tumors-might-grow-faster-night
[B] ]G Dinkov - https://raypeatforum.com/community/threads/cancer-grows-more-at-night-under-the-influence-of-cortisol.4962/
[C] LAURIOLA M, ENUKA Y ZEISEL A YARDEN Y, 2014. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment - Published: 03 October 2014 Mattia Lauriola, Nature Communications volume 5, Article number: 5073 (2014)
“Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR’s positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR’s feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.
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“Interestingly, tumours differed not only by their size but also by their appearance, suggesting that the administration of Lapatinib during the resting phase also inhibited tumour angiogenesis (Fig. 6f, right panel), in line with a similar effect of an anti-HER2 antibody when tested in animals39. Taken together with the in vitro studies and observations made with genetically modified mice, the effect of timing on drug efficacy not only adds another line of evidence in support of our model, but also proposes a potential strategy capable of augmenting the therapeutic effects of anticancer drugs”.[...]
The observations we made in animal models and analyses of patient specimens favour circadian regulation of RTKs by the HPA neuroendocrine axis. Our model and tumour xenograft studies further offer a strategy to enhance the therapeutic impact of anti-RTK cancer drugs, by means of careful scheduling of drug administration. [...] Our tumour xenograft studies lend support to this model, meaning that cancer patients might derive higher benefit from chronotherapy rather than constant rate infusion of RTK-targeting drugs.
How to cite this article: Lauriola, M. et al. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment. Nat. Commun. 5:5073 doi: 10.1038/ncomms6073 (2014).
References:
1. Troyer, K. L. & Lee, D. C. Regulation of mouse mammary gland development and tumorigenesis by the ERBB signaling network. J. Mammary Gland. Biol. Neoplasia 6, 7–21 (2001).
Article CAS PubMed Google Scholar
2. Wintermantel, T. M., Bock, D., Fleig, V., Greiner, E. F. & Schutz, G. The epithelial glucocorticoid receptor is required for the normal timing of cell proliferation during mammary lobuloalveolar development but is dispensable for milk production. Mol. Endocrinol. 19, 340–349 (2005).
Article CAS PubMed Google Scholar
3. den Hollander, P., Savage, M. I. & Brown, P. H. Targeted therapy for breast cancer prevention. Front. Oncol. 3, 250 (2013).
Article PubMed PubMed Central Google Scholar
4. Hynes, N. E. & Watson, C. J. Mammary gland growth factors: roles in normal development and in cancer. Cold Spring Harb. Perspect. Biol. 2, a003186 (2010).
Article PubMed PubMed Central Google Scholar
5. Avraham, R. & Yarden, Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat. Rev. Mol. Cell Biol. 12, 104–117 (2011).
Article CAS PubMed Google Scholar
6. Kadmiel, M. & Cidlowski, J. A. Glucocorticoid receptor signaling in health and disease. Trends Pharmacol. Sci. 34, 518–530 (2013).
Article CAS PubMed PubMed Central Google Scholar
7. Surjit, M. et al. Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145, 224–241 (2011).
Article CAS PubMed Google Scholar
8. Stocklin, E., Wissler, M., Gouilleux, F. & Groner, B. Functional interactions between Stat5 and the glucocorticoid receptor. Nature 383, 726–728 (1996).
Article ADS CAS PubMed Google Scholar
9. Herr, I., Gassler, N., Friess, H. & Buchler, M. W. Regulation of differential pro- and anti-apoptotic signaling by glucocorticoids. Apoptosis 12, 271–291 (2007).
Article CAS PubMed Google Scholar
10. Herr, I. & Pfitzenmaier, J. Glucocorticoid use in prostate cancer and other solid tumours: implications for effectiveness of cytotoxic treatment and metastases. Lancet Oncol. 7, 425–430 (2006).
Article CAS PubMed Google Scholar
11. Greene, M. W. Circadian rhythms and tumor growth. Cancer Lett. 318, 115–123 (2012).
Article CAS PubMed Google Scholar
12. Hermes, G. L. et al. Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors. Proc. Natl Acad. Sci. USA 106, 22393–22398 (2009).
Article ADS CAS PubMed PubMed Central Google Scholar
13. Holsboer, F. & Ising, M. Stress hormone regulation: biological role and translation into therapy. Annu. Rev. Psychol. 61, 81–109 C101-111 (2010).
14. Muthuswamy, S. K., Li, D., Lelievre, S., Bissell, M. J. & Brugge, J. S. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat. Cell Biol. 3, 785–792 (2001).
Article CAS PubMed PubMed Central Google Scholar
15. Tarcic, G. et al. EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF. FASEB J. 26, 1582–1592 (2012).
Article CAS PubMed PubMed Central Google Scholar
16. Daemen, A. et al. Modeling precision treatment of breast cancer. Genome Biol. 14, R110 (2013).
Article PubMed PubMed Central Google Scholar
17. Zeisel, A. et al. qCMA: a desktop application for quantitative collective cell migration analysis. J. Biomol. Screen. 18, 356–360 (2012).
18. Kostler, W. J. et al. Epidermal growth-factor—induced transcript isoform variation drives mammary cell migration. PLoS ONE 8, e80566 (2013).
Article ADS PubMed PubMed Central Google Scholar
19. Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000).
Article ADS CAS PubMed Google Scholar
20. Mason, J. M., Morrison, D. J., Basson, M. A. & Licht, J. D. Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol. 16, 45–54 (2006).
Article CAS PubMed Google Scholar
21. Ikeda, Y., Kumagai, H., Skach, A., Sato, M. & Yanagisawa, M. Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155, 1323–1336 (2013).
Article CAS PubMed PubMed Central Google Scholar
22. Wilson, K. J. et al. EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors (Chur, Switzerland) 30, 107–116 (2012).
23. Chrousos, G. P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. New Engl. J. Med. 332, 1351–1362 (1995).
Article CAS PubMed Google Scholar
24. Smith, G. W. et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20, 1093–1102 (1998).
Article CAS PubMed Google Scholar
25. Kollet, O. et al. Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors. Leukemia 27, 2006–2015 (2013).
Article CAS PubMed Google Scholar
26. Arteaga, C. L. et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 9, 16–32 (2012).
27. Yarden, Y. & Pines, G. The ERBB network: at last, cancer therapy meets systems biology. Nat. Rev. Cancer 12, 553–563 (2012).
Article CAS PubMed Google Scholar
28. Spector, N. L. et al. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J. Clin. Oncol. 23, 2502–2512 (2005).
Article CAS PubMed Google Scholar
29. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).
Article ADS CAS PubMed Google Scholar
30. Pan, D., Kocherginsky, M. & Conzen, S. D. Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res. 71, 6360–6370 (2011).
Article CAS PubMed PubMed Central Google Scholar
31. Hung, M. C. On mammary gland growth factors: roles in normal development and in cancer. Cold Spring Harb. Perspect. Biol. 4, a013532 (2012).
PubMed PubMed Central Google Scholar
32. Gerber, A. et al. Blood-borne circadian signal stimulates daily oscillations in actin dynamics and SRF activity. Cell 152, 492–503 (2013).
Article CAS PubMed Google Scholar
33. Rich, T. et al. Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin. Cancer Res. 11, 1757–1764 (2005).
Article CAS PubMed Google Scholar
34. Cao, Y. et al. Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans. Blood 121, 1553–1562 (2013).
Article CAS PubMed PubMed Central Google Scholar
35. Sanchis, A., Bayo, P., Sevilla, L. M. & Perez, P. Glucocorticoid receptor antagonizes EGFR function to regulate eyelid development. Int. J. Dev. Biol. 54, 1473–1480 (2010).
Article CAS PubMed Google Scholar
36. Ayroldi, E. et al. Mechanisms of the anti-inflammatory effects of glucocorticoids: genomic and nongenomic interference with MAPK signaling pathways. FASEB J. 26, 4805–4820 (2012).
Article CAS PubMed Google Scholar
37. Alon, U. Network motifs: theory and experimental approaches. Nat. Rev. Genet. 8, 450–461 (2007).
Article CAS PubMed Google Scholar
38. Amit, I. et al. A module of negative feedback regulators defines growth factor signaling. Nat. Genet. 39, 503–512 (2007).
Article CAS PubMed Google Scholar
39. Tsuchiya, Y., Minami, I., Kadotani, H., Todo, T. & Nishida, E. Circadian clock-controlled diurnal oscillation of Ras/ERK signaling in mouse liver. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 89, 59–65 (2013).
Article CAS PubMed PubMed Central Google Scholar
40. Scheving, L. A., Tsai, T. H., Cornett, L. E., Feuers, R. J. & Scheving, L. E. Circadian variation of epidermal growth factor receptor in mouse liver. Anat. Rec. 224, 459–465 (1989).
Article CAS PubMed Google Scholar
41. Dorscheid, D. R. et al. Effects of corticosteroid-induced apoptosis on airway epithelial wound closure in vitro. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L794–L801 (2006).
Article CAS PubMed Google Scholar
42. Demaria, S. et al. Cancer and inflammation: promise for biologic therapy. J. Immunother. 33, 335–351 (2010).
Article PubMed PubMed Central Google Scholar
43. Ulrich, C. M., Bigler, J. & Potter, J. D. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat. Rev. Cancer 6, 130–140 (2006).
Article CAS PubMed Google Scholar
44. Ying, H. et al. Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proc. Natl Acad. Sci. USA 107, 6912–6917 (2010).
Article ADS CAS PubMed PubMed Central Google Scholar
45. Filipski, E. et al. Host circadian clock as a control point in tumor progression. J. Natl Cancer Inst. 94, 690–697 (2002).
46. Kramer, A. et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511–2515 (2001).
Article ADS CAS PubMed Google Scholar
47. Sephton, S. E., Sapolsky, R. M., Kraemer, H. C. & Spiegel, D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J. Natl Cancer Inst. 92, 994–1000 (2000).
Article CAS PubMed Google Scholar
48. Nakagawa, H. et al. Basis for dosing time-dependent change in the anti-tumor effect of imatinib in mice. Biochem. Pharmacol. 72, 1237–1245 (2006).
Article CAS PubMed Google Scholar
49. Levi, F., Okyar, A., Dulong, S., Innominato, P. F. & Clairambault, J. Circadian timing in cancer treatments. Annu. Rev. Pharmacol. Toxicol. 50, 377–421 (2010).
Article CAS PubMed Google Scholar
Disponível em: https://www.nature.com/articles/ncomms6073
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