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Mechanisms of cancer dissemination along nerves

Opinion | Published: 06 May 2016

Mechanisms of cancer dissemination along nerves

Nature Reviews Cancer volume16, pages399–408 (2016) | Download Citation

Abstract

The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.

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References

  1. 1.Liebig, C., Ayala, G., Wilks, J. A., Berger, D. H. & Albo, D. Perineural invasion in cancer: a review of the literature. Cancer 115, 3379–3391 (2009).
  2. 2.Amit, M. et al. International collaborative validation of intraneural invasion as a prognostic marker in adenoid cystic carcinoma of the head and neck. Head Neck 37, 1038–1045 (2015).
  3. 3.Chatterjee, D. et al. Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma. Am. J. Surg. Pathol. 36, 409–417 (2012).
  4. 4.Cheng, L. et al. Preoperative prediction of surgical margin status in patients with prostate cancer treated by radical prostatectomy. J. Clin. Oncol. 18, 2862–2868 (2000).
  5. 5.Batsakis, J. G. Nerves and neurotropic carcinomas. Ann. Otol. Rhinol. Laryngol. 94, 426–427 (1985).
  6. 6.Dodd, G. D., Dolan, P. A., Ballantyne, A. J., Ibanez, M. L. & Chau, P. The dissemination of tumors of the head and neck via the cranial nerves. Radiol. Clin. North Am. 8, 445–461 (1970).
  7. 7.Ballantyne, A. J., McCarten, A. B. & Ibanez, M. L. The extension of cancer of the head and neck through peripheral nerves. Am. J. Surg. 106, 651–667 (1963).
  8. 8.Hassan, M. O. & Maksem, J. The prostatic perineural space and its relation to tumor spread: an ultrastructural study. Am. J. Surg. Pathol. 4, 143–148 (1980).
  9. 9.Rodin, A. E., Larson, D. L. & Roberts, D. K. Nature of the perineural space invaded by prostatic carcinoma. Cancer 20, 1772–1779 (1967).
  10. 10.Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
  11. 11.Scanlon, C. S. et al. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer. Nat. Commun. 6, 6885 (2015).
  12. 12.Ayala, G. E. et al. Stromal antiapoptotic paracrine loop in perineural invasion of prostatic carcinoma. Cancer Res. 66, 5159–5164 (2006).
  13. 13.Gil, Z. et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J. Natl Cancer Inst. 102, 107–118 (2010).
  14. 14.Ayala, G. E. et al. Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res. 64, 6082–6090 (2004).
  15. 15.Yang, G., Wheeler, T. M., Kattan, M. W., Scardino, P. T. & Thompson, T. C. Perineural invasion of prostate carcinoma cells is associated with reduced apoptotic index. Cancer 78, 1267–1271 (1996).
  16. 16.Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008).
  17. 17.Lindsay, T. H. et al. Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression. Pain 119, 233–246 (2005).
  18. 18.Jobling, P. et al. Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res. 75, 1777–1781 (2015).
  19. 19.Demir, I. E. et al. Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis. PLoS ONE 8, e60529 (2013).
  20. 20.Cavel, O. et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res. 72, 5733–5743 (2012).
  21. 21.Bockman, D. E., Buchler, M. & Beger, H. G. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage. Gastroenterology 107, 219–230 (1994).
  22. 22.Park, D. S. et al. Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. J. Neurosci. 20, 3104–3114 (2000).
  23. 23.Zhang, Y. et al. Pim-1 kinase as activator of the cell cycle pathway in neuronal death induced by DNA damage. J. Neurochem. 112, 497–510 (2010).
  24. 24.Demir, I. E. et al. Neural invasion in pancreatic cancer: the past, present and future. Cancers (Basel) 2, 1513–1527 (2010).
  25. 25.Bapat, A. A., Hostetter, G., Von Hoff, D. D. & Han, H. Perineural invasion and associated pain in pancreatic cancer. Nat. Rev. Cancer 11, 695–707 (2011).
  26. 26.Tuxhorn, J. A. et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin. Cancer Res. 8, 2912–2923 (2002).
  27. 27.Coulpier, M., Anders, J. & Ibanez, C. F. Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survival. J. Biol. Chem. 277, 1991–1999 (2002).
  28. 28.De Oliveira, T. et al. Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. Mol. Cancer 11, 19 (2012).
  29. 29.Swanson, B. J. et al. MUC1 is a counter-receptor for myelin-associated glycoprotein (Siglec-4a) and their interaction contributes to adhesion in pancreatic cancer perineural invasion. Cancer Res. 67, 10222–10229 (2007).
  30. 30.Marchesi, F. et al. The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res. 68, 9060–9069 (2008).
  31. 31.Moos, M. et al. Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin. Nature 334, 701–703 (1988).
  32. 32.Abiatari, I. et al. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma. Mol. Cancer Ther. 8, 1494–1504 (2009).
  33. 33.Burnett, M. G. & Zager, E. L. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg. Focus 16, E1 (2004).
  34. 34.Marchesi, F. et al. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J. Neuroimmunol. 224, 39–44 (2010).
  35. 35.He, S. et al. The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Mol. Cancer Res. 13, 380–390 (2015).
  36. 36.Ben, Q. W. et al. Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. Ann. Surg. Oncol. 17, 2213–2221 (2010).
  37. 37.Ayala, G. E. et al. Bystin in perineural invasion of prostate cancer. Prostate 66, 266–272 (2006).
  38. 38.Ammer, A. G. et al. Saracatinib impairs head and neck squamous cell carcinoma invasion by disrupting invadopodia function. J. Cancer Sci. Ther. 1, 52–61 (2009).
  39. 39.Li, X. et al. Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin. Cancer Res. 20, 4326–4338 (2014).
  40. 40.Karja, V. et al. Tumour-infiltrating lymphocytes: a prognostic factor of PSA-free survival in patients with local prostate carcinoma treated by radical prostatectomy. Anticancer Res. 25, 4435–4438 (2005).
  41. 41.Vesalainen, S., Lipponen, P., Talja, M. & Syrjanen, K. Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur. J. Cancer 30A, 1797–1803 (1994).
  42. 42.Schwartz, E. S. et al. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140, 1283–1291 (2011).
  43. 43.Schwartz, E. S. et al. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J. Neurosci. 33, 5603–5611 (2013).
  44. 44.Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).
  45. 45.Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).
  46. 46.Van Steenwinckel, J. et al. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J. Neurosci. 31, 5865–5875 (2011).
  47. 47.Amit, M., Na’ara S., Binenbaum, Y. & Gil, Z. Marrow-derived macrophages mediate invasion of pancreatic adenocarcinoma by RET activation. Cancer Res. 75 (15 Suppl.), 2355 (2015).
  48. 48.Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).
  49. 49.Vonlaufen, A. et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 68, 2085–2093 (2008).
  50. 50.Apte, M. V. et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29, 179–187 (2004).
  51. 51.Ceyhan, G. O. et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology 136, 177–186 (2009).
  52. 52.Samkharadze, T. et al. Pigment epithelium-derived factor associates with neuropathy and fibrosis in pancreatic cancer. Am. J. Gastroenterol. 106, 968–980 (2011).
  53. 53.Apte, M. V., Wilson, J. S., Lugea, A. & Pandol, S. J. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144, 1210–1219 (2013).
  54. 54.Friess, H. et al. Enhanced expression of TGF-betas and their receptors in human acute pancreatitis. Ann. Surg. 227, 95–104 (1998).
  55. 55.Masamune, A., Watanabe, T., Kikuta, K. & Shimosegawa, T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin. Gastroenterol. Hepatol. 7, S48–S54 (2009).
  56. 56.Tang, D. et al. Pancreatic satellite cells derived galectin-1 increase the progression and less survival of pancreatic ductal adenocarcinoma. PLoS ONE 9, e90476 (2014).
  57. 57.Hsia, D. A. et al. Differential regulation of cell motility and invasion by FAK. J. Cell Biol. 160, 753–767 (2003).
  58. 58.Pantel, K. & Brakenhoff, R. H. Dissecting the metastatic cascade. Nat. Rev. Cancer 4, 448–456 (2004).
  59. 59.Scholz, J. & Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361–1368 (2007).
  60. 60.Gaudet, A. D., Popovich, P. G. & Ramer, M. S. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J. Neuroinflamm. 8, 110 (2011).
  61. 61.Demir, I. E. et al. Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J. Natl Cancer Inst. 106, dju184 (2014).
  62. 62.Chan, J. R., Cosgaya, J. M., Wu, Y. J. & Shooter, E. M. Neurotrophins are key mediators of the myelination program in the peripheral nervous system. Proc. Natl Acad. Sci. USA 98, 14661–14668 (2001).
  63. 63.Chen-Tsai, C. P., Colome-Grimmer, M. & Wagner, R. F. Jr. Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB, TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas. Dermatol. Surg. 30, 1009–1016 (2004).
  64. 64.Sakamoto, Y. et al. Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma. Oncol. Rep. 8, 477–484 (2001).
  65. 65.Ivanov, S. V. et al. TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior. Oncogene 32, 3698–3710 (2013).
  66. 66.Airaksinen, M. S. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394 (2002).
  67. 67.He, S. et al. GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc. Natl Acad. Sci. USA 111, E2008–E2017 (2014).
  68. 68.Wang, K. et al. The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer. Carcinogenesis 35, 103–113 (2014).
  69. 69.Ceyhan, G. O. et al. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann. Surg. 244, 274–281 (2006).
  70. 70.Iwahashi, N. et al. Expression of glial cell line-derived neurotrophic factor correlates with perineural invasion of bile duct carcinoma. Cancer 94, 167–174 (2002).
  71. 71.Esseghir, S. et al. A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha1 receptor up-regulation in breast cancer. Cancer Res. 67, 11732–11741 (2007).
  72. 72.Paratcha, G. et al. Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29, 171–184 (2001).
  73. 73.Carlomagno, F. et al. The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res. 62, 1077–1082 (2002).
  74. 74.Klein, R., Jing, S. Q., Nanduri, V., O’Rourke, E. & Barbacid, M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65, 189–197 (1991).
  75. 75.Zhu, Z. et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J. Clin. Oncol. 17, 2419–2428 (1999).
  76. 76.Zhang, S. et al. Chemokine CXCL12 and its receptor CXCR4 expression are associated with perineural invasion of prostate cancer. J. Exp. Clin. Cancer Res. 27, 62 (2008).
  77. 77.Geldof, A. A., De Kleijn, M. A., Rao, B. R. & Newling, D. W. Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells. J. Cancer Res. Clin. Oncol. 123, 107–112 (1997).
  78. 78.Liebl, F. et al. The severity of neural invasion is associated with shortened survival in colon cancer. Clin. Cancer Res. 19, 50–61 (2013).
  79. 79.Andres, R. et al. Multiple effects of artemin on sympathetic neurone generation, survival and growth. Development 128, 3685–3695 (2001).
  80. 80.Gao, L., Bo, H., Wang, Y., Zhang, J. & Zhu, M. Neurotrophic factor artemin promotes invasiveness and neurotrophic function of pancreatic adenocarcinoma in vivo and in vitro. Pancreas 44, 134–143 (2015).
  81. 81.Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).
  82. 82.Sawai, H. et al. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 65, 11536–11544 (2005).
  83. 83.Vinuesa, C. G., Tangye, S. G., Moser, B. & Mackay, C. R. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 5, 853–865 (2005).
  84. 84.El-Haibi, C. P., Singh, R., Sharma, P. K., Singh, S. & Lillard, J. W. Jr. CXCL13 mediates prostate cancer cell proliferation through JNK signalling and invasion through ERK activation. Cell Prolif. 44, 311–319 (2011).
  85. 85.Zhu, Z. et al. CXCL13–CXCR5 axis promotes the growth and invasion of colon cancer cells via PI3K/AKT pathway. Mol. Cell. Biochem. 400, 287–295 (2015).
  86. 86.Singh, S. et al. Clinical and biological significance of CXCR5 expressed by prostate cancer specimens and cell lines. Int. J. Cancer 125, 2288–2295 (2009).
  87. 87.Qi, X. W. et al. Expression features of CXCR5 and its ligand, CXCL13 associated with poor prognosis of advanced colorectal cancer. Eur. Rev. Med. Pharmacol. Sci. 18, 1916–1924 (2014).
  88. 88.Feng, Y. J., Zhang, B. Y., Yao, R. Y. & Lu, Y. Muscarinic acetylcholine receptor M3 in proliferation and perineural invasion of cholangiocarcinoma cells. Hepatobiliary Pancreat. Dis. Int. 11, 418–423 (2012).
  89. 89.Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
  90. 90.Entschladen, F., Drell, T. L.t., Lang, K., Joseph, J. & Zaenker, K. S. Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol. 5, 254–258 (2004).
  91. 91.Li, Z. J. & Cho, C. H. Neurotransmitters, more than meets the eye—neurotransmitters and their perspectives in cancer development and therapy. Eur. J. Pharmacol. 667, 17–22 (2011).
  92. 92.Kiba, T. Relationships between the autonomic nervous system and the pancreas including regulation of regeneration and apoptosis: recent developments. Pancreas 29, e51–e58 (2004).
  93. 93.Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A. & Sood, A. K. Sympathetic nervous system regulation of the tumour microenvironment. Nat. Rev. Cancer 15, 563–572 (2015).
  94. 94.Kim-Fuchs, C. et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 40–47 (2014).
  95. 95.Guo, K. et al. Interaction of the sympathetic nerve with pancreatic cancer cells promotes perineural invasion through the activation of STAT3 signaling. Mol. Cancer Ther. 12, 264–273 (2013).
  96. 96.Palma, C. Tachykinins and their receptors in human malignancies. Curr. Drug Targets 7, 1043–1052 (2006).
  97. 97.Hokfelt, T., Pernow, B. & Wahren, J. Substance P: a pioneer amongst neuropeptides. J. Intern. Med. 249, 27–40 (2001).
  98. 98.Li, X. et al. Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells. Mol. Cancer Res. 11, 294–302 (2013).
  99. 99.Banerjee, R., Henson, B. S., Russo, N., Tsodikov, A. & D’Silva, N. J. Rap1 mediates galanin receptor 2-induced proliferation and survival in squamous cell carcinoma. Cell Signal. 23, 1110–1118 (2011).
  100. 100.Sugimoto, T. et al. The galanin signaling cascade is a candidate pathway regulating oncogenesis in human squamous cell carcinoma. Genes Chromosomes Cancer 48, 132–142 (2009).
  101. 101.Henson, B. S. et al. Galanin receptor 1 has anti-proliferative effects in oral squamous cell carcinoma. J. Biol. Chem. 280, 22564–22571 (2005).
  102. 102.Merati, K. et al. Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters. Am. J. Clin. Oncol. 24, 447–452 (2001).
  103. 103.Behrens, J. The role of cell adhesion molecules in cancer invasion and metastasis. Breast Cancer Res. Treat. 24, 175–184 (1993).
  104. 104.Roy, L. D. et al. MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30, 1449–1459 (2011).
  105. 105.Schafer, M. K. & Altevogt, P. L1CAM malfunction in the nervous system and human carcinomas. Cell. Mol. Life Sci. 67, 2425–2437 (2010).
  106. 106.Gavert, N., Ben-Shmuel, A., Raveh, S. & Ben-Ze’ev, A. L1-CAM in cancerous tissues. Expert Opin. Biol. Ther. 8, 1749–1757 (2008).
  107. 107.Kiefel, H. et al. L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression. Oncogene 29, 4766–4778 (2010).
  108. 108.Kiefel, H., Pfeifer, M., Bondong, S., Hazin, J. & Altevogt, P. Linking L1CAM-mediated signaling to NF-κB activation. Trends Mol. Med. 17, 178–187 (2011).
  109. 109.Romano, N. H., Madl, C. M. & Heilshorn, S. C. Matrix RGD ligand density and L1CAM-mediated Schwann cell interactions synergistically enhance neurite outgrowth. Acta Biomater. 11, 48–57 (2015).
  110. 110.Raveh, S., Gavert, N. & Ben-Ze’ev, A. L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 282, 137–145 (2009).
  111. 111.Jansson, K. H. et al. Identification of β-2 as a key cell adhesion molecule in PCa cell neurotropic behavior: a novel ex vivo and biophysical approach. PLoS ONE 9, e98408 (2014).
  112. 112.Sroka, I. C. et al. The laminin binding integrin α6β1 in prostate cancer perineural invasion. J. Cell. Physiol. 224, 283–288 (2010).
  113. 113.Aoki, R. & Fukuda, M. N. Recent molecular approaches to elucidate the mechanism of embryo implantation: trophinin, bystin, and tastin as molecules involved in the initial attachment of blastocysts to the uterus in humans. Semin. Reprod. Med. 18, 265–271 (2000).
  114. 114.Fukuda, M. N. & Nozawa, S. Trophinin, tastin, and bystin: a complex mediating unique attachment between trophoblastic and endometrial epithelial cells at their respective apical cell membranes. Semin. Reprod. Endocrinol. 17, 229–234 (1999).
  115. 115.Zhang, Y. et al. The Chk1/Cdc25A pathway as activators of the cell cycle in neuronal death induced by camptothecin. J. Neurosci. 26, 8819–8828 (2006).
  116. 116.Galbiati, F. et al. Expression of caveolin-1 and -2 in differentiating PC12 cells and dorsal root ganglion neurons: caveolin-2 is up-regulated in response to cell injury. Proc. Natl Acad. Sci. USA 95, 10257–10262 (1998).
  117. 117.Dai, H. et al. Pim-2 upregulation: biological implications associated with disease progression and perineural invasion in prostate cancer. Prostate 65, 276–286 (2005).
  118. 118.Fox, C. J. et al. The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev. 17, 1841–1854 (2003).
  119. 119.Zhang, B., Zhang, Y., Dagher, M. C. & Shacter, E. Rho GDP dissociation inhibitor protects cancer cells against drug-induced apoptosis. Cancer Res. 65, 6054–6062 (2005).
  120. 120.Zhang, Y. & Zhang, B. D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res. 66, 5592–5598 (2006).
  121. 121.Eugenin, E. A. & Berman, J. W. Chemokine-dependent mechanisms of leukocyte trafficking across a model of the blood–brain barrier. Methods 29, 351–361 (2003).
  122. 122.Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).
  123. 123.Na’ara, S., Gil, Z. & Amit, M. Paracrine interactions between Schwann cells and cancer cells promotes perineural invasion via L1cam secretion. Cancer Res. AACR 2016 Annual Meeting, abstract 5072 (2016).
  124. 124.Takahashi, T. et al. Perineural invasion by ductal adenocarcinoma of the pancreas. J. Surg. Oncol. 65, 164–170 (1997).
  125. 125.Hirai, I. et al. Perineural invasion in pancreatic cancer. Pancreas 24, 15–25 (2002).
  126. 126.Duraker, N., Sisman, S. & Can, G. The significance of perineural invasion as a prognostic factor in patients with gastric carcinoma. Surg. Today 33, 95–100 (2003).
  127. 127.He, P. et al. Multivariate statistical analysis of clinicopathologic factors influencing survival of patients with bile duct carcinoma. World J. Gastroenterol. 8, 943–946 (2002).
  128. 128.Su, C. H. et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann. Surg. 223, 384–394 (1996).
  129. 129.Nagakawa, T. et al. Perineural invasion of carcinoma of the pancreas and biliary tract. Br. J. Surg. 80, 619–621 (1993).
  130. 130.Maru, N., Ohori, M., Kattan, M. W., Scardino, P. T. & Wheeler, T. M. Prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens. Hum. Pathol. 32, 828–833 (2001).
  131. 131.Lee, I. H. et al. Perineural invasion is a marker for pathologically advanced disease in localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 68, 1059–1064 (2007).
  132. 132.Carter, R. L., Foster, C. S., Dinsdale, E. A. & Pittam, M. R. Perineural spread by squamous carcinomas of the head and neck: a morphological study using antiaxonal and antimyelin monoclonal antibodies. J. Clin. Pathol. 36, 269–275 (1983).
  133. 133.Fagan, J. J. et al. Perineural invasion in squamous cell carcinoma of the head and neck. Arch. Otolaryngol. Head Neck Surg. 124, 637–640 (1998).
  134. 134.Soo, K. C. et al. Prognostic implications of perineural spread in squamous carcinomas of the head and neck. Laryngoscope 96, 1145–1148 (1986).
  135. 135.Goepfert, H., Dichtel, W. J., Medina, J. E., Lindberg, R. D. & Luna, M. D. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am. J. Surg. 148, 542–547 (1984).
  136. 136.Liebig, C. et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J. Clin. Oncol. 27, 5131–5137 (2009).
  137. 137.Horn, A., Dahl, O. & Morild, I. Venous and neural invasion as predictors of recurrence in rectal adenocarcinoma. Dis. Colon Rectum 34, 798–804 (1991).
  138. 138.Matsushima, T., Mori, M., Kido, A., Adachi, Y. & Sugimachi, K. Preoperative estimation of neural invasion in rectal carcinoma. Oncol. Rep. 5, 73–76 (1998).
  139. 139.Krasna, M. J., Flancbaum, L., Cody, R. P., Shneibaum, S. & Ben Ari, G. Vascular and neural invasion in colorectal carcinoma. Incidence and prognostic significance. Cancer 61, 1018–1023 (1988).
  140. 140.Schaefer, A. W. et al. Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization. J. Biol. Chem. 274, 37965–37973 (1999).
  141. 141.Silletti, S. et al. Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion. J. Biol. Chem. 279, 28880–28888 (2004).

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Acknowledgements

C. Cohen is thanked for her editorial assistance. N. Rada is thanked for her artistic work. Supported by the Israeli Science Foundation, Binational US–Israel Science Foundation, Israeli Cancer Research Found, Israel Cancer Association, Rappaport Institute at the Technion and the Clinical Research Institute at Rambam.

Author information

Affiliations

  1. Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel.
    • Moran Amit
    • , Shorook Na’ara
    •  & Ziv Gil

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ziv Gil.

Supplementary information

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  1. 1.Supplementary informationSupplementary information S1 (table)

Glossary

Desmoplastic reaction

Also known as desmoplasia, the desmoplastic reaction is the growth of fibrous tissue secondary to an insult such as a tumour or surgery.Dorsal root ganglia

(DRG). Also known as spinal ganglia, DRG are clusters of nerve cell bodies (a ganglia) in a posterior root of a spinal nerve.Endoneurial space

The anatomical space between the deepest layer of nerve covering, called the endoneurium, and the peripheral nerve fibres.Euclidean velocity

Directional vector of velocity defined not only by magnitude, but also by direction.Pancreatic afferents

These afferent nerve fibres are sensory neurons extending far from the nerve cell body in the coeliac ganglia. They conduct pain sensation by carrying nerve impulses from sensory receptors towards the central nervous system.Parasympathetic cholinergic fibres

These components of the autonomic nervous system are responsible for the body’s activities when it is at rest. They are called cholinergic after the main neurotransmitter, acetylcholine.Perineural space

The anatomical space between the most superficial nerve covering, also known as the epineurium layer, and the middle layer, called the perineurium, in peripheral nerves.Perineurium

Peripheral fibres are each wrapped in a protective sheath known as the endoneurium. These are bundled together into fascicles, each surrounded by a protective sheath known as the perineurium.Peripheral glial cell

Schwann cells are the principal peripheral glial cells that function to support neurons in the peripheral nervous system.Sensory fibres

Nerve fibres that deliver sensory information (for example, pain), from a peripheral organ to the central nervous system.Sympathetic nervous system

A component of the autonomic nervous system responsible for maintaining homeostasis and stimulating the body for flight-or-fight response. In peripheral nerves, the main postganglionic sympathetic neurotransmitter is noradrenaline, which activates α- and β-adrenergic receptors.Visceral hypersensitivity

Cancer-associated altered visceral perception caused by hyperexcitability of the neurons in the visceral afferent nervous system. Characterized by a lowered threshold for abdominal pain and discomfort.Wallerian degeneration

A process that results after a nerve injury, in which the part of the axon separated from the cell body of the neuron degenerates distal to the injury.

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06 May 2016

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https://doi.org/10.1038/nrc.2016.38

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´´The world people need to have very efficient researches and projects resulting in very innovative drugs, vaccines, therapeutical substances, medical devices and other technologies according to the age, the genetics and medical records of the person. So, the treatment, diagnosis and prognosis will be very efficient and better, of course´´. Rodrigo Nunes Cal ´´O mundo precisa ter pesquisas e projetos muito eficientes que resultem em medicamentos, vacinas, substâncias terapêuticas, dispositivos médicos e outras tecnologias muito inovadoras de acordo com a idade, a genética e o prontuário da pessoa. Assim, o tratamento, o diagnóstico e o prognóstico serão bem mais eficientes e melhores, é claro´´. Rodrigo Nunes Cal ´´As you know, the world needs to have very efficient researches resulting new therapeutical substances, medical devices, prevention, diagnostic and prognostic methods, drugs and vaccines, for example. Very detailed researches are fundamental in this process. So, high impact innovations are essential to the world people!!´´ Rodrigo Nunes Cal  ´´Como você sabe, o mundo precisa de pesquisas muito eficientes que resultem em novas substâncias terapêuticas, aparelhos médicos, métodos de prevenção, de diagnósticos e de prognósticos, medicamentos e vacinas, por exemplo. Pesquisas muito detalhadas são fundamentais neste processo, obviamente. Portanto, inovações de grande impacto são essenciais para as pessoas do mundo todo!!´´ Rodrigo Nunes Cal ´´Ter grandes metas, muitas das quais ditas como impossíveis é muito importante porque pode induzir de várias maneiras em diferentes intensidades na sociedade científica mundial o surgimento de grandes descobertas científicas para toda a humanidade, beneficiando significativamente a vida das pessoas e fazendo com que a expectativa de vida humana aumente significativamente. Dessa forma, doenças conhecidas hoje como sendo fatais e incuráveis, podem se tornar doenças curáveis, com a obtenção de novas tecnologias altamente eficazes de prevenção, diagnóstico, prognóstico e de tratamento´´. Rodrigo Nunes Cal ´´Having big goals, many of which are said to be impossible, is very important because it can induce, in different ways, in different intensities in the world scientific society, the emergence of great scientific discoveries for all of humanity, significantly benefiting people's lives and causing the increase of human life expectancy significantly. Thus, diseases known today as being fatal and incurable, can become curable diseases, with the achievement of highly effective prevention, diagnosis, prognosis and treatment technologies´´. Rodrigo Nunes Cal * ´´The very unknown path may be the best path to take in life´´. Rodrigo Nunes Cal ´´O caminho muito desconhecido pode ser o melhor caminho a seguir na vida´´. Rodrigo Nunes Cal ´´A Ciência abre um leque de possibilidades dos mais variados assuntos e dos mais variados níveis de dificuldades. Sendo assim, a compreensão total dos mecanismos fisiológicos envolvidos na patogênese das doenças, destacando-se as doenças fatais que ocorrem em humanos, é de suma importância para a humanidade, com toda certeza. Quem sabe num futuro próximo essa compreensão seja muito bem entendida e quem sabe, como muitas pessoas sonham na imortalidade física, dentre elas cientistas, essa grande conquista pode ser adquirida. Como você sabe, a humanidade necessita urgentemente de novas descobertas científicas, destacando-se a aquisição de medicamentos e vacinas altamente eficazes contra um grande número de doenças, dentre elas as doenças desconhecidas e silenciosas, a obtenção de aparelhos médicos muito eficientes de diagnóstico, prognóstico e tratamento de doenças, entre outros. Com certeza, precisamos ter esperança e motivação para a realização de ótimos trabalhos e para uma qualidade de vida bem melhor e uma expectativa de vida cada vez maior´´. Rodrigo Nunes Cal ´´Science opens up a range of possibilities for the most varied subjects and the most varied levels of difficulties. Therefore, the full understanding of the physiological mechanisms involved in the pathogenesis of diseases, highlighting the fatal diseases that occur in humans, is of paramount importance for humanity, for sure. Maybe in the near future this understanding will be very well understood and who knows, as many people dream of physical immortality, among them scientists, this great achievement can be acquired. As you know, humanity urgently needs new scientific discoveries, highlighting the acquisition of highly effective medicines and vaccines against a large number of diseases, including unknown and silent diseases, obtaining very efficient medical devices for diagnosis, prognosis and treatment of diseases, among others. Certainly, we need to have hope and motivation to do great work and for a much better quality of life and an ever-increasing life expectancy´´. Rodrigo Nunes Cal - Note: The statistics on the number of people who visited this blog in 2018 were not entirely based on real visitors. As estatísticas sobre número de pessoas que acessaram este blog no ano de 2018 não foram totalmente baseadas em visitantes reais. ´´Great difficulties may have come, but it is of great importance to have in mind the possibility of great victories in the future, bringing happiness and health for a long time´´. Rodrigo Nunes Cal ´´O caminho muito desconhecido pode ser o melhor caminho a seguir na vida´´. Rodrigo Nunes Cal ´´Understanding the great difficulties of a given subject can be a very long process, however, of great value for the progress of Science in all aspects´´. Rodrigo Nunes Cal ´´Entender as grandes dificuldades de um determinado assunto pode ser um processo muito longo, mas de grande valor para o progresso da Ciência em todos os seus aspectos´´. Rodrigo Nunes Cal My Curriculum Lattes: http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4240145A2 My Facebook Page: www.facebook.com/scientificblog IT´S A VERY EASY, FAST AND PRACTICAL WAY TO KNOW EXCELLENT INFORMATION ABOUT SCIENCE, TECHNOLOGY AND INNOVATION, AS AN EXAMPLE, APPLYING THE SEARCH MECHANISM Ctrl + F IN THIS BLOG FOR A WORD OR WORDS. SO, THIS BLOG SHARING IS VERY IMPORTANT TO THE WORLD SOCIETY! I hope in some way with this blog to help significantly in the socio-economic and technical-scientific development of the countries. E-mails: rodrigoncal1984@gmail.com rodrigonunescal@yahoo.com calrodrigonunes@gmail.com rodrigoncal1984@yahoo.com ´´NÃO VÁ PARA ONDE O CAMINHO PODE TE LEVAR. VÁ ONDE NÃO HÁ CAMINHO E DEIXE UMA TRILHA. ´´ ´´DON'T GO WHERE THE PATH CAN TAKE YOU. GO WHERE THERE IS NO PATH AND LEAVE A TRAIL. ´´ @ KNOWING THE UNKNOWN.. CONHECENDO O DESCONHECIDO.. The world needs very innovative ideas to people live better and longer more and more. I have been invited as a Speaker/Delegate in numerous International Conferences and Congresses. * DISCOVERING HOW THE INITIAL STAGES OF A CERTAIN DISEASES WORK, SUCH AS A FATAL DISEASES, IS OF HUGE IMPORTANCE FOR SCIENCE, FOR SURE. THERE ARE SEVERAL BIOLOGICAL FACTORS CONNECTED IN THE HUMAN BODY THAT ACTING IN A VERY COMPLEX FORM. THEREFORE, IT IS OF GREAT NECESSITY TO CARRY OUT NEW SCIENTIFIC RESEARCHES MUCH MORE DETAILED AND MODERN, WITH A HIGH DEGREE OF PRECISION, EVEN IF THERE IS NO SIGNIFICANT STATISTICAL DIFFERENCE BETWEEN CERTAIN FACTORS. * DESCOBRIR COMO FUNCIONA OS ESTÁGIOS INICIAIS DE DETERMINADAS DOENÇAS, TAIS COMO AS DOENÇAS FATAIS, É DE ENORME IMPORTÂNCIA PARA A CIÊNCIA , COM CERTEZA. HÁ VÁRIOS FATORES BIOLÓGICOS INTERLIGADOS NO CORPO HUMANO QUE ATUAM DE FORMA MUITO COMPLEXA. PORTANTO, É DE GRANDE NECESSIDADE A REALIZAÇÃO DE NOVAS PESQUISAS CIENTÍFICAS MUITO MAIS MINUCIOSAS E MODERNAS, COM ALTO GRAU DE PRECISÃO, MESMO QUE NÃO HAJA DIFERENÇA ESTATÍSTICA SIGNIFICATIVA ENTRE DETERMINADOS FATORES. * The discussion of certain facts in science envolving stastistics is fundamental to the scientific community, for example, the analysis and interpretation of very important, innovative and interesting graphics with no statistical difference between them can have a big value to the researches and to the future researches. So, the quality and efficiency of researches can increase so much in a little time, increasing the possiblities of excellent references and new scientific discoveries. The facts veracity and the disclosure of them are essential for the scientific community, of course. Reconhecer o(s) erro(s) cometido(s) e não praticá-lo(s) novamente é um ato de grande sabedoria e importância para si mesmo e para a(s) outra(s) pessoa(s). Acknowledging mistakes and not doing them again is an act of great wisdom and importance for yourself and to the other person or people. ´´O IMPOSSÍVEL PODE SER POSSÍVEL´´. ´´THE IMPOSSIBLE CAN BE POSSIBLE´´. I have received positive feedbacks about this blog by LinkedIn, Twitter, Facebook, E-mails and Instagram. ´´EVERYONE DIES. THE GOAL IS NOT TO LIVE FOREVER. THE GOAL S TO CREATE SOMETHING THAT WILL´´ # time #time #internet #technologies #HighTechnologies #Cell Phones #Computer #Notebook  # Television #radio #communication #tempo  #InternetSociety # Society #person # people # age #ages #genetics #longevity #investigations #researches #efficiency #projects #ideas #reference #references #article #articles #journal # journals #magazines #websites #blogs #sites #links #SocialNetworks #energy #graphics #dissertation #monograph #citations #ImpactFactor #pesquisa #pesquisas #tecnologias #DiferentesPercepções #DifferentPerceptions #mind #mente #minds #MentesHumanas #emails #email e-mails reading #MenteHumana leitura mensagem mensagens probabilidade(s) probabilities messages message importance importância relevância assunto(s) subject subjects issue tema reflexão reflections vision visão pioneirismo pionners prêmio(s) prizes awards innovations inovações Grupos de Estudo Grupos Controle saúde doença(s) nome(s) tempo(s) Início da doença - Momento inicial da doença - Momento(s) inicial(ais) da(s) doença(s) humana(s) - Semelhança genética com camundongos - Mice researches - vaccines - drugs - eficiência - medicamento(s) - vacina(s) - High efficiency - Fatal diseases - Doenças fatais - Investments - investimentos - laboratórios - industries - indústrias - laboratories - Centros de Pesquisa - Países - cidades - cities - longevidade - desafio(s) - challenges - gráficos detalhados - interações biológicas - fatores biológicas - análise minuciosa - Very detailed analysis @ Initial moment of disease - Initial moments of human diseases - No Name @ discussion - discussão científica - science facts - detailed graphics - fatos científicos - publicação de trabalhos científicos - publications - hard work - better results - better science - diagnóstico - prognósticos - Diferença Estatística Significativa 100 Diferença Estatística Significativa @ Significant Statistical Difference - V X I Interpretations interpretações intenções intenions countries EU 100 gene Sem genes Cem genes 1 0 0 gene(s) time(s) times 100 limites limite(s) limits 1 0 0 limit NO LIMIT 10 0 @ 100 genes @ 100 gene & NO GENE NO TEMPO NOS TEMPOS NO(S) TEMPO(S) NOS TIMES NO TIME 100 GENE No Time # no time @ nos genes no(s) gene(s) * no(s) limite(s) - words- palavra(s) - listen - write - type - fala - escuta - ler - virtualidade - virtuality - reality - realidade - mundo real - mundo virtual - vida real - virtual life - real life - vida virtual - imaginations - thoughts - pensamento(s) - imaginações - melhoria - improvement - respect - respeito - speak - nome(s) - trabalho(s) - dinheiro - money - team - equipe - objetivo(s) - Best Universities of the World - Scientific Discoveries - Brazil - World - RNA - Cell - DNA - Idade biológica - biological age - pessoas - idade - idade(s) - pessoa - História da Computação Mundial - Harvard - Names - Places - City - researches - scientists - professors - pesquisador(es) - cientistas - professores - professor(es) - Produção científica - Fatores de Impacto - feelings - logic - sentimento(s) - lógica - história - world history - difficulties - dificuldades - Scientific community - comunidade científica mundial - vidas humanas - vida(s) humana(s) - trabalho(s) - human lives - life - human life - única - one life - person people @ momentos - moments memories memory memória longevidade energias energia(s) Many people liked my Twitter and Facebook comments that I informed this blog like great professors, scientists and researchers around the world who work in human health area! Many data about it aren´t in this blog. #database #system #time #data #search #information #InternetHistory #contribuitions #improvement #analysis #intentions Intenções @ #person #people #age #longevity #work #reading #probabilities #energy #money #price #clicks #jobs #country #city #countries #cities #knowledge #HumanInterdependence #WorldHistory #communication #HumanRelations #websites #e-mails #SocialNetworks #ranking #links #images #photos #texts #messages #videos #writing #typing #speak #listen #think #feelings #ideas #ScientificDiscoveries #investigations #researches #articles #ImpactFactors #journals #citations #influence #dissertations #monographs #ScientificWorks #Inventions #graphics #subjects #books #references #blogs ´´Compreender as grandes dificuldades de um determinado assunto pode ser um processo muito demorado, porém, de grande valia para o progresso da Ciência em todos os aspectos´´ Rodrigo Nunes Cal Observação/Note: I won a scholarship by FAPEMIG during the period of ´´my´´ monograph in Uberaba. Ganhei bolsa de estudo pela FAPEMIG durante o período da ´´minha´´ monografia em Uberaba. During the period that I participated of ´´my´´ dissertation at FAMERP, I didn't win a scholarship. Já durante o mestrado que fiz na FAMERP, não ganhei bolsa de estudo. ´´Os gráficos baseados em dados da ´´minha´´ dissertação que fiz podem ser uma excelente referência para muitos tipos de pesquisas e projetos, é claro !! Por exemplo, para pesquisas e projetos que tenham como objetivo analisar os tipos de influências das idades em camundongos e humanos (estudos genéticos, por exemplo) em relação a diferentes estágios de determinadas doenças, como aquelas em que a comunidade científica desconhece (doenças desconhecidas) e que poderão surgir no mundo. Outros tipos de pesquisas e projetos que podem ser feitos são aqueles que analisam a eficácia de diversos tipos de substâncias terapêuticas em camundongos e humanos nos diversos tipos de doenças com o objetivo de saber qual a melhor substância terapêutica para cada doença, levando em consideração a idade e genética, com certeza. Contudo, realizar pesquisas com o objetivo de avaliar qual é a influência da idade e da genética na eficiência terapêutica em animais de experimentação e em humanos, consequentemente, possui um grande valor, já que muitas pessoas adoecem e acabam falecendo mesmo sendo submetidas à ótimos sistemas de diagnóstico, tratamento e prognóstico, dependendo da doença que possui e do estágio da mesma´´. ´´A partir daí, ao comprovar que há influência significativa da idade e da genética, consequentemente, no processo de patogênese de doenças nos animais de experimentação e nos humanos, seria muito mais conveniente e lógico um grupo de indivíduos de certa faixa etária e histórico familiar e individual de doenças adquiridas e possíveis de serem adquiridas no decorrer do tempo serem tratados com outros tipos de medicamentos, substâncias terapêuticas, vacinas, dentre outros. Com certeza, para a realização destes tipos de pesquisa deve haver grande investimento financeiro nos laboratórios a fim de aquisição de aparelhos científicos altamente eficientes. Com certeza, pesquisas à nível genético e com relação à influência da idade do ser vivo na patogênese de doenças, até das doenças desconhecidas pelo mundo científico. O fato é que este tipo de pesquisa é muito importante porque como todos sabem, há muitas doenças que voltam a se manifestar nas pessoas mesmo depois de excelentes tratamentos, dos mais variados tipos. E outro ponto a ser refletido é a permanência de doenças fatais´´. ´´Assim, este tipo de influência da idade e consequentemente da genética na fisiopatologia das doenças hereditárias ou não hereditárias, um indivíduo de uma determinada idade será submetido a um tratamento terapêutico diferente de outro com a mesma doença mas com idade diferente da de até a pesquisa mostrou uma influência significativa na patogênese da doença, portanto, utilizará outro tipo de substância terapêutica, medicamentos, entre outros. Isso certamente acontecerá se a comunidade científica mundial comprovar cientificamente essas hipóteses por meio de várias pesquisas e projetos científicos. As pessoas precisam ter excelentes inovações para a expectativa de vida humana aumentar muito rapidamente cada vez mais. Portanto, quanto mais a medicina personalizada for, melhor será para cada um de nós´´. Rodrigo Nunes Cal ´´The graphics based on data from ´´my´´ dissertation I did can be an excellent reference for many types of researches and projects, of course!! For example, for researches and projects that the goals are analyse the type of influences of ages in mice and human (genetic studies, for example) in relation to different stages of determined diseases, like those that the scientific community do not know about them (unknown diseases). Other types of researches and projects that can be done is those that analyse the efficiency of many types of therapeutical substances in mice and human in many types of diseases with the objective of knowing which is the best therapeutic substance for each disease, taking into account age and genetics, for sure. For example, to carry out research with the objective of evaluating the influence of age and genetics on therapeutic efficiency in experimental animals and in humans´´. ´´Thus, by proving that there is a significant influence of age and genetics, consequently, in the process of pathogenesis of diseases in experimental animals and in humans, it would be much more convenient and logical to have a group of individuals of a certain age group and family and individual history of acquired diseases and possible to be acquired over time being treated with other types of drugs, therapeutic substances, vaccines, among others. Certainly, to carry out these types of research there must be a large financial investment in laboratories in order to acquire highly efficient scientific devices. Certainly, research at the genetic level and regarding the influence of the age of the living being on the pathogenesis of diseases, even diseases unknown to the scientific world. The fact is that this type of research is very important because as everyone knows, there are many diseases that come back to manifest in people even after excellent treatments, of the most varied types. And another point to be reflected on is the permanence of fatal diseases´´. ´´Taking into account this type of influence of age and consequently genetics on the pathophysiology of inherited or not inherited diseases, an individual of a certain age will be submitted to a different therapeutic treatment from another with the same disease but who has a different age than through the research has shown a significant influence on the pathogenesis of the disease, therefore, will use another type of therapeutic substance, medicine, among others. This will certainly happen if the world scientific community scientifically proves these hypotheses through various research and scientific projects. So, the people need to have excellent innovation to the human expectancy  of life increase so much faster more and more´´. Rodrigo Nunes Cal Note/Obs: I thought each person could do their own friend request permission setting since Facebook's technology is so big, for example. Eu achava que cada pessoa poderia fazer sua própria configuração de permissão de solicitação de amizade já que a tecnologia do Facebook é muito grande, por exemplo.

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