Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pancreatic cancer cachexia: three dimensions of a complex syndrome

British Journal of Cancer volume 124, pages 1623–1636 (2021)Cite this article

Subjects

Abstract

Cancer cachexia is a multifactorial syndrome that is characterised by a loss of skeletal muscle mass, is commonly associated with adipose tissue wasting and malaise, and responds poorly to therapeutic interventions. Although cachexia can affect patients who are severely ill with various malignant or non-malignant conditions, it is particularly common among patients with pancreatic cancer. Pancreatic cancer often leads to the development of cachexia through a combination of distinct factors, which, together, explain its high prevalence and clinical importance in this disease: systemic factors, including metabolic changes and pathogenic signals related to the tumour biology of pancreatic adenocarcinoma; factors resulting from the disruption of the digestive and endocrine functions of the pancreas; and factors related to the close anatomical and functional connection of the pancreas with the gut. In this review, we conceptualise the various insights into the mechanisms underlying pancreatic cancer cachexia according to these three dimensions to expose its particular complexity and the challenges that face clinicians in trying to devise therapeutic interventions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Conceptualisation of the three dimensions involved in the development of pancreatic cancer cachexia.
Fig. 2: Tumour-derived factors associated with cachexia in pancreatic adenocarcinoma.
Fig. 3: Impaired pancreatic exocrine and endocrine function interact with alterations in the digestive tract to promote pancreatic cancer cachexia.

Similar content being viewed by others

References

  1. Fearon, K., Strasser, F., Anker, S. D., Bosaeus, I., Bruera, E., Fainsinger, R. L. et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 12, 489–495 (2011).

    Article  PubMed  Google Scholar 

  2. Baracos, V. E., Martin, L., Korc, M., Guttridge, D. C. & Fearon, K. C. H. Cancer-associated cachexia. Nat. Rev. Dis. Primers 4, 17105 (2018).

    Article  PubMed  Google Scholar 

  3. Martin, L., Birdsell, L., MacDonald, N., Reiman, T., Clandinin, M. T., McCargar, L. J. et al. Cancer cachexia in the age of obesity: skeletal muscle depletion Is a powerful prognostic factor, independent of body mass index. J. Clin. Oncol. 31, 1539–1547 (2013).

    Article  PubMed  Google Scholar 

  4. Minicozzi, P., Cassetti, T., Vener, C. & Sant, M. Analysis of incidence, mortality and survival for pancreatic and biliary tract cancers across Europe, with assessment of influence of revised European age standardisation on estimates. Cancer Epidemiol. 55, 52–60 (2018).

    Article  PubMed  Google Scholar 

  5. Hendifar, A. E., Chang, J. I., Huang, B. Z., Tuli, R. & Wu, B. U. Cachexia, and not obesity, prior to pancreatic cancer diagnosis worsens survival and is negated by chemotherapy. J. Gastrointest. Oncol. 9, 17–23 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mitsunaga S., Kasamatsu E. & Machii K. Incidence and frequency of cancer cachexia during chemotherapy for advanced pancreatic ductal adenocarcinoma. Support Care Cancer 28, 5271–5279 (2020)

  7. Kays, J. K., Shahda, S., Stanley, M., Bell, T. M., O’Neill, B. H., Kohli, M. D. et al. Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer. J. Cachexia Sarcopenia Muscle 9, 673–684 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Choi, Y., Oh, D. Y., Kim, T. Y., Lee, K. H., Han, S. W., Im, S. A. et al. Skeletal muscle depletion predicts the prognosis of patients with advanced pancreatic cancer undergoing palliative chemotherapy, independent of body mass index. PLoS ONE 10, e0139749 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Bachmann, J., Heiligensetzer, M., Krakowski-Roosen, H., Buchler, M. W., Friess, H. & Martignoni, M. E. Cachexia worsens prognosis in patients with resectable pancreatic cancer. J. Gastrointest. Surg. 12, 1193–1201 (2008).

    Article  PubMed  Google Scholar 

  10. Bauer, M. R., Bright, E. E., MacDonald, J. J., Cleary, E. H., Hines, O. J. & Stanton, A. L. Quality of life in patients with pancreatic cancer and their caregivers. Pancreas 47, 368–375 (2018).

    Article  PubMed  Google Scholar 

  11. Hagensen, A., London, A. E., Phillips, J. J., Helton, W. S., Picozzi, V. J. & Blackmore, C. C. Using experience-based design to improve the care experience for patients with pancreatic cancer. J. Oncol. Pract. 12, e1035–e1041 (2016).

    Article  PubMed  Google Scholar 

  12. Waddell, N., Pajic, M., Patch, A. M., Chang, D. K., Kassahn, K. S., Bailey, P. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guillaumond, F., Leca, J., Olivares, O., Lavaut, M.-N., Vidal, N., Berthezène, P. et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 110, 3919–3924 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen, Y., Cairns, R., Papandreou, I., Koong, A. & Denko, N. C. Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. PLoS ONE 4, e7033 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Wang, F., Liu, H., Hu, L., Liu, Y., Duan, Y., Cui, R. et al. The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells. BMC Cancer 18, 360 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Roux, C., Riganti, C., Borgogno, S. F., Curto, R., Curcio, C., Catanzaro, V. et al. Endogenous glutamine decrease is associated with pancreatic cancer progression. Oncotarget 8, 95361–95376 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Vasseur, S., Tomasini, R., Tournaire, R. & Iovanna, J. L. Hypoxia induced tumor metabolic switch contributes to pancreatic cancer aggressiveness. Cancers (Basel) 2, 2138–2152 (2010).

    Article  CAS  Google Scholar 

  20. Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mayers, J. R., Wu, C., Clish, C. B., Kraft, P., Torrence, M. E., Fiske, B. P. et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 20, 1193–1198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Neinast, M. D., Jang, C., Hui, S., Murashige, D. S., Chu, Q., Morscher, R. J. et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metabolism 29, 417–429.e414 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Mayers, J. R., Torrence, M. E., Danai, L. V., Papagiannakopoulos, T., Davidson, S. M., Bauer, M. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, J. H., Cho, Y. R., Kim, J. H., Kim, J., Nam, H. Y., Kim, S. W. et al. Branched-chain amino acids sustain pancreatic cancer growth by regulating lipid metabolism. Exp. Mol. Med. 51, 1–11 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Das, S. K., Eder, S., Schauer, S., Diwoky, C., Temmel, H., Guertl, B. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Ryden, M., Agustsson, T., Laurencikiene, J., Britton, T., Sjolin, E., Isaksson, B. et al. Lipolysis–not inflammation, cell death, or lipogenesis–is involved in adipose tissue loss in cancer cachexia. Cancer 113, 1695–1704 (2008).

    Article  PubMed  Google Scholar 

  27. Shaw, J. H. & Wolfe, R. R. Fatty acid and glycerol kinetics in septic patients and in patients with gastrointestinal cancer. The response to glucose infusion and parenteral feeding. Ann. Surg. 205, 368–376 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, F., Kumagai-Braesch, M., Herrington, M. K., Larsson, J. & Permert, J. Increased lipid metabolism and cell turnover of MiaPaCa2 cells induced by high-fat diet in an orthotopic system. Metabolism 58, 1131–1136 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Agustsson, T., Ryden, M., Hoffstedt, J., van Harmelen, V., Dicker, A., Laurencikiene, J. et al. Mechanism of increased lipolysis in cancer cachexia. Cancer Res. 67, 5531–5537 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Russell, S. T. & Tisdale, M. J. Effect of a tumour-derived lipid-mobilising factor on glucose and lipid metabolism in vivo. Br. J. Cancer 87, 580–584 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Russell, S. T., Zimmerman, T. P., Domin, B. A. & Tisdale, M. J. Induction of lipolysis in vitro and loss of body fat in vivo by zinc-alpha2-glycoprotein. Biochim. Biophys. Acta 59–68, 2004 (1636).

    Google Scholar 

  32. Bao, Y., Bing, C., Hunter, L., Jenkins, J. R. & Wabitsch, M. Trayhurn P. Zinc-α2-glycoprotein, a lipid mobilizing factor, is expressed and secreted by human (SGBS) adipocytes. FEBS Lett. 579, 41–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Bing, C., Bao, Y., Jenkins, J., Sanders, P., Manieri, M., Cinti, S. et al. Zinc-α2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proc. Natl Acad. Sci. USA 101, 2500–2505 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kulyte, A., Lorente-Cebrian, S., Gao, H., Mejhert, N., Agustsson, T., Arner, P. et al. MicroRNA profiling links miR-378 to enhanced adipocyte lipolysis in human cancer cachexia. Am. J. Physiol. Endocrinol. Metab. 306, E267–E274 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Sagar, G., Sah, R. P., Javeed, N., Dutta, S. K., Smyrk, T. C., Lau, J. S. et al. Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. Gut 65, 1165–1174 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Rohm M., Zeigerer A., Machado J. & Herzig S. Energy metabolism in cachexia. EMBO Rep. 20, e47258 (2019)

  37. Mitsunaga, S., Ikeda, M., Shimizu, S., Ohno, I., Furuse, J., Inagaki, M. et al. Serum levels of IL-6 and IL-1beta can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer. Br. J. Cancer 108, 2063–2069 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Petruzzelli, M., Schweiger, M., Schreiber, R., Campos-Olivas, R., Tsoli, M., Allen, J. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20, 433–447 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Sah, R. P., Sharma, A., Nagpal, S., Patlolla, S. H., Sharma, A., Kandlakunta, H. et al. Phases of metabolic and soft tissue changes in months preceding a diagnosis of pancreatic ductal adenocarcinoma. Gastroenterology 156, 1742–1752 (2019).

    Article  PubMed  Google Scholar 

  40. Bing, C., Russell, S. T., Beckett, E. E., Collins, P., Taylor, S., Barraclough, R. et al. Expression of uncoupling proteins-1, -2 and -3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor. Br. J. Cancer 86, 612–618 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Falconer, J. S., Fearon, K. C., Plester, C. E., Ross, J. A. & Carter, D. C. Cytokines the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann. Surg. 219, 325–331 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gonzalez-Bulnes, A., Fujiwara, Y., Kobayashi, T., Chayahara, N., Imamura, Y., Toyoda, M. et al. Metabolomics evaluation of serum markers for cachexia and their intra-day variation in patients with advanced pancreatic cancer. PLoS ONE 9, e113259 (2014).

    Article  CAS  Google Scholar 

  43. Bye, A., Wesseltoft-Rao, N., Iversen, P. O., Skjegstad, G., Holven, K. B., Ulven, S. et al. Alterations in inflammatory biomarkers and energy intake in cancer cachexia: a prospective study in patients with inoperable pancreatic cancer. Med. Oncol. 33, 54 (2016).

    Article  PubMed  CAS  Google Scholar 

  44. Bachmann, J., Buchler, M. W., Friess, H. & Martignoni, M. E. Cachexia in patients with chronic pancreatitis and pancreatic cancer: impact on survival and outcome. Nutr. Cancer 65, 827–833 (2013).

    Article  PubMed  Google Scholar 

  45. Talar-Wojnarowska, R., Gasiorowska, A., Smolarz, B., Romanowicz-Makowska, H., Kulig, A. & Malecka-Panas, E. Clinical significance of interleukin-6 (Il-6) gene polymorphism and Il-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig. Dis. Sci. 54, 683–689 (2008).

    Article  PubMed  CAS  Google Scholar 

  46. Miura, T., Mitsunaga, S., Ikeda, M., Shimizu, S., Ohno, I., Takahashi, H. et al. Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels. Pancreas 44, 756–763 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Talbert, E. E., Lewis, H. L., Farren, M. R., Ramsey, M. L., Chakedis, J. M., Rajasekera, P. et al. Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-naive pancreatic cancer patients. J. Cachexia Sarcopenia Muscle 9, 358–368 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hou, Y.-C., Wang, C.-J., Chao, Y.-J., Chen, H.-Y., Wang, H.-C., Tung, H.-L. et al. Elevated serum interleukin-8 level correlates with cancer-related cachexia and sarcopenia: An indicator for pancreatic cancer outcomes. J. Clin. Med. 7, 502 (2018).

    Article  PubMed Central  Google Scholar 

  49. Martignoni, M. E. Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia. Clin. Cancer Res. 11, 5802–5808 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Zhang, D., Zhou, Y., Wu, L., Wang, S., Zheng, H., Yu, B. et al. Association of IL-6 gene polymorphisms with cachexia susceptibility and survival time of patients with pancreatic cancer. Ann. Clin. Lab. Sci. 38, 113–119 (2008).

    CAS  PubMed  Google Scholar 

  51. Egberts, J. H., Cloosters, V., Noack, A., Schniewind, B., Thon, L., Klose, S. et al. Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 68, 1443–1450 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. de Matos-Neto, E. M., Lima, J. D. C. C., de Pereira, W. O., Figuerêdo, R. G., Riccardi, D. M. D. R., Radloff, K. et al. Systemic inflammation in cachexia - Is tumor cytokine expression profile the culprit? Front. Immunol. 6, 629–629 (2015).

    PubMed  PubMed Central  Google Scholar 

  53. Shimada, M., Andoh, A., Araki, Y., Fujiyama, Y. & Bamba, T. Ligation of the Fas antigen stimulates chemokine secretion in pancreatic cancer cell line PANC-11. J. Gastroenterol. Hepatol. 16, 1060–1067 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Delitto, D., Judge, S. M., Delitto, A. E., Nosacka, R. L., Rocha, F. G., DiVita, B. B. et al. Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia. Oncotarget 8, 1177–1189 (2017).

    Article  PubMed  Google Scholar 

  55. Gerber, M. H., Underwood, P. W., Judge, S. M., Delitto, D., Delitto, A. E., Nosacka, R. L. et al. Local and systemic cytokine profiling for pancreatic ductal adenocarcinoma to study cancer cachexia in an era of precision medicine. Int. J. Mol. Sci. 19, 3836 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  56. Haugen, F., Labori, K. J., Noreng, H. J., Buanes, T., Iversen, P. O. & Drevon, C. A. Altered expression of genes in adipose tissues associated with reduced fat mass in patients with pancreatic cancer. Arch. Physiol. Biochem. 117, 78–87 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Bonetto, A., Aydogdu, T., Jin, X., Zhang, Z., Zhan, R., Puzis, L. et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am. J. Physiol. Endocrinol. Metab. 303, E410–E421 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pettersen, K., Andersen, S., Degen, S., Tadini, V., Grosjean, J., Hatakeyama, S. et al. Cancer cachexia associates with a systemic autophagy-inducing activity mimicked by cancer cell-derived IL-6 trans-signaling. Sci. Rep. 7, 2046 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Ma, J. F., Sanchez, B. J., Hall, D. T., Tremblay, A. K., Di Marco, S. & Gallouzi, I. E. STAT3 promotes IFNgamma/TNFalpha-induced muscle wasting in an NF-kappaB-dependent and IL-6-independent manner. EMBO Mol. Med. 9, 622–637 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hall, D. T., Ma, J. F., Di Marco, S. & Gallouzi, I.-E. Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia. Aging 3, 702–715 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Acharyya, S., Ladner, K. J., Nelsen, L. L., Damrauer, J., Reiser, P. J., Swoap, S. et al. Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J. Clin. Invest. 114, 370–378 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gilabert, M., Calvo, E., Airoldi, A., Hamidi, T., Moutardier, V., Turrini, O. et al. Pancreatic cancer-induced cachexia Is Jak2-dependent in mice. J. Cell Physiol. 229, 1437–1443 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Zimmers, T. A., Fishel, M. L. & Bonetto, A. STAT3 in the systemic inflammation of cancer cachexia. Semin. Cell. Dev. Biol. 54, 28–41 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lira, F. S., Yamashita, A. S., Rosa, J. C., Tavares, F. L., Caperuto, E., Carnevali, L. C. Jr. et al. Hypothalamic inflammation is reversed by endurance training in anorectic-cachectic rats. Nutr. Metab. 8, 60–60 (2011).

    Article  CAS  Google Scholar 

  65. Plata-Salamán, C. R., Ilyin, S. E. & Gayle, D. Brain cytokine mRNAs in anorectic rats bearing prostate adenocarcinoma tumor cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 275, R566–R573 (1998).

    Article  Google Scholar 

  66. Inui, A. & Neuropeptide, Y. a key molecule in anorexia and cachexia in wasting disorders? Mol. Med. Today 5, 79–85 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Reyes, T. M. & Sawchenko, P. E. Involvement of the arcuate nucleus of the hypothalamus in interleukin-1-induced anorexia. J. Neurosci. 22, 5091–5099 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Amitani, M., Asakawa, A., Amitani, H. & Inui, A. Control of food intake and muscle wasting in cachexia. Int. J. Biochem. Cell Biol. 45, 2179–2185 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Ji, Y. B., Bo, C. L., Xue, X. J., Weng, E. M., Gao, G. C., Dai, B. B. et al. Association of inflammatory cytokines with the symptom cluster of pain, fatigue, depression, and sleep disturbance in chinese patients with cancer. J. Pain Symptom Manage 54, 843–852 (2017).

    Article  PubMed  Google Scholar 

  70. Breitbart, W., Rosenfeld, B., Tobias, K., Pessin, H., Ku, G. Y., Yuan, J. et al. Depression, cytokines, and pancreatic cancer. Psychooncology 23, 339–345 (2014).

    Article  PubMed  Google Scholar 

  71. Yaskin, J. C. Nervous symptoms as earliest manifestations of carcinoma of the pancreas. JAMA 96, 1664–1668 (1931).

    Article  Google Scholar 

  72. Morley, J. E. Anorexia of aging: physiologic and pathologic. Am. J. Clin. Nutr. 66, 760–773 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Moo-Young, T. A., Larson, J. W., Belt, B. A., Tan, M. C., Hawkins, W. G., Eberlein, T. J. et al. Tumor-derived TGF-beta mediates conversion of CD4+Foxp3+ regulatory T cells in a murine model of pancreas cancer. J. Immunother. 32, 12–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Löhr, M., Schmidt, C., Ringel, J., Kluth, M., Müller, P., Nizze, H. et al. Transforming Growth Factor-β1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 61, 550–555 (2001).

    PubMed  Google Scholar 

  75. Zugmaier, G., Paik, S., Wilding, G., Knabbe, C., Bano, M., Lupu, R. et al. Transforming Growth Factor β1 induces cachexia and szystemic fibrosis without an antitumor effect in nude mice. Cancer Res. 51, 3590–3594 (1991).

    CAS  PubMed  Google Scholar 

  76. Mendias, C. L., Gumucio, J. P., Davis, M. E., Bromley, C. W., Davis, C. S. & Brooks, S. V. Transforming growth factor-beta induces skeletal muscle atrophy and fibrosis through the induction of atrogin-1 and scleraxis. Muscle Nerve 45, 55–59 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Greco, S. H., Tomkotter, L., Vahle, A. K., Rokosh, R., Avanzi, A., Mahmood, S. K. et al. TGF-beta blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia. PLoS ONE 10, e0132786 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Zimmers, T. A., Davies, M. V., Koniaris, L. G., Haynes, P., Esquela, A. F., Tomkinson, K. N. et al. Induction of cachexia in mice by systemically administered myostatin. Science 296, 1486–1488 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Chen, J. L., Walton, K. L., Winbanks, C. E., Murphy, K. T., Thomson, R. E., Makanji, Y. et al. Elevated expression of activins promotes muscle wasting and cachexia. FASEB J. 28, 1711–1723 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Zhong, X., Pons, M., Poirier, C., Jiang, Y., Liu, J., Sandusky, G. E. et al. The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy. J. Cachexia Sarcopenia Muscle 10, 1083–1101 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Koopmann, J., Buckhaults, P., Brown, D. A., Zahurak, M. L., Sato, N., Fukushima, N. et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin. Cancer Res. 10, 2386–2392 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Johnen, H., Lin, S., Kuffner, T., Brown, D. A., Tsai, V. W., Bauskin, A. R. et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat. Med. 13, 1333–1340 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Todorov, P., Cariuk, P., McDevitt, T., Coles, B., Fearon, K. & Tisdale, M. Characterization of a cancer cachectic factor. Nature 379, 739–742 (1996).

    Article  CAS  PubMed  Google Scholar 

  84. Whitehouse, A. S. & Tisdale, M. J. Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB. Br. J. Cancer 89, 1116–1122 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wyke, S. M. & Tisdale, M. J. NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle. Br. J. Cancer 92, 711–721 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Eley, H. L. & Tisdale, M. J. Skeletal muscle atrophy, a link between depression of protein synthesis and increase in degradation. J. Biol. Chem. 282, 7087–7097 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Wigmore, S. J., Todorov, P. T., Barber, M. D., Ross, J. A., Tisdale, M. J. & Fearon, K. C. H. Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor. Br. J. Surg. 87, 53–58 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Watchorn, T. M., Waddell, I. D., Dowidar, N. & Ross, J. A. Proteolysis-inducing factor regulates hepatic gene expression via the transcription factors NF-κΒ and STAT3. FASEB J. 15, 562–564 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Huang, X.-Y., Huang, Z.-L., Yang, J.-H., Xu, Y.-H., Sun, J.-S., Zheng, Q. et al. Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting. J Exp. Clin. Cancer Res. 35, 46 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. He, W. A., Calore, F., Londhe, P., Canella, A., Guttridge, D. C. & Croce, C. M. Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7. Proc. Natl Acad. Sci USA 111, 4525–4529 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang, G., Liu, Z., Ding, H., Zhou, Y., Doan, H. A., Sin, K. W. T. et al. Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90. Nat. Commun 8, 589 (2017)

  92. Sikkens, E. C. M., Cahen, D. L., de Wit, J., Looman, C. W. N., van Eijck, C. & Bruno, M. J. A prospective assessment of the natural course of the exocrine pancreatic function in patients with a pancreatic head tumor. J. Clin. Gastroenterol. 48, e43–e46 (2014).

    Article  PubMed  Google Scholar 

  93. Permert, J., Ihse, I., Jorfeldt, L., von Schenck, H., Arnqvist, H. J. & Larsson, J. Pancreatic cancer is associated with impaired glucose metabolism. Eur. J. Surg. 159, 101–107 (1993).

    CAS  PubMed  Google Scholar 

  94. Lim, P.-W., Dinh, K. H., Sullivan, M., Wassef, W. Y., Zivny, J., Whalen, G. F. et al. Thirty-day outcomes underestimate endocrine and exocrine insufficiency after pancreatic resection. HPB (Oxford) 18, 360–366 (2016).

    Article  Google Scholar 

  95. Maignan, A., Ouaissi, M., Turrini, O., Regenet, N., Loundou, A., Louis, G. et al. Risk factors of exocrine and endocrine pancreatic insufficiency after pancreatic resection: A multi-center prospective study. J. Visc. Surg. 155, 173–181 (2018).

    Article  CAS  PubMed  Google Scholar 

  96. Speicher, J. E. & Traverso, L. W. Pancreatic exocrine function is preserved after distal pancreatectomy. J. Gastroenterol. Surg. 14, 1006–1011 (2010).

    Article  Google Scholar 

  97. Beger, H. G., Poch, B., Mayer, B. & Siech, M. New onset of diabetes and pancreatic exocrine insufficiency after pancreaticoduodenectomy for benign and malignant tumors. Ann. Surg. 267, 259–270 (2018).

    Article  PubMed  Google Scholar 

  98. Kang, M. J., Jung, H. S., Jang, J.-Y., Jung, W., Chang, J., Shin, Y. C. et al. Metabolic effect of pancreatoduodenectomy: resolution of diabetes mellitus after surgery. Pancreatology 16, 272–277 (2016).

    Article  PubMed  Google Scholar 

  99. Wu, J.-M., Kuo, T.-C., Yang, C.-Y., Chiang, P.-Y., Jeng, Y.-M., Huang, P.-H. et al. Resolution of diabetes after pancreaticoduodenectomy in patients with and without pancreatic ductal cell adenocarcinoma. Ann. Surg. Oncol. 20, 242–249 (2013).

    Article  PubMed  Google Scholar 

  100. Vujasinovic, M., Valente, R., Del Chiaro, M., Permert, J. & Löhr, J.-M. Pancreatic exocrine insufficiency in pancreatic cancer. Nutrients 9, 183 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  101. Schober, M., Jesenofsky, R., Faissner, R., Weidenauer, C., Hagmann, W., Michl, P. et al. Desmoplasia and chemoresistance in pancreatic cancer. Cancers (Basel) 6, 2137–2154 (2014).

    Article  Google Scholar 

  102. Brune, K., Abe, T., Canto, M., O’Malley, L., Klein, A. P., Maitra, A. et al. Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am. J. Surg. Pathol. 30, 1067–1076 (2006).

    PubMed  PubMed Central  Google Scholar 

  103. Anagnostides, A., Chadwick, V., Selden, A. & Maton, P. Sham feeding and pancreatic secretion: evidence for direct vagal stimulation of enzyme output. Gastroenterology 87, 109–114 (1984).

    Article  CAS  PubMed  Google Scholar 

  104. White, T., McAlexander, R. & Magee, D. The effect of gastric distension on duodenal aspirates in man. Gastroenterology 44, 48–51 (1963).

    Article  CAS  PubMed  Google Scholar 

  105. Watanabe, S., Shiratori, K., Takeuchi, T., Chey, W., You, C. & Chang, T.-M. Release of cholecystokinin and exocrine pancreatic secretion in response to an elemental diet in human subjects. Dig. Dis. Sci. 31, 919–924 (1986).

    Article  CAS  PubMed  Google Scholar 

  106. 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).

    Article  CAS  PubMed  Google Scholar 

  107. Ceyhan, G. O., Demir, I. E., Rauch, U., Bergmann, F., Muller, M. W., Buchler, M. W. et al. Pancreatic neuropathy results in “neural remodeling” and altered pancreatic innervation in chronic pancreatitis and pancreatic cancer. Am. J. Gastroenterol. 104, 2555–2565 (2009).

    Article  PubMed  Google Scholar 

  108. Körner, M., Hayes, G. M., Rehmann, R., Zimmermann, A., Friess, H., Miller, L. J. et al. Secretin receptors in normal and diseased human pancreas: marked reduction of receptor binding in ductal neoplasia. Am. J. Patho. 167, 959–968 (2005).

    Article  Google Scholar 

  109. Weinberg, D. S., Ruggeri, B., Barber, M. T., Biswas, S., Miknyocki, S., Waldman, S. A. & Cholecystokinin, A. and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma. J. Clin. Invest. 100, 597–603 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Weinberg, D. S., Heyt, G. J., Cavanagh, M., Pitchon, D., McGlynn, K. A. & London, W. T. Cholecystokinin and gastrin levels are not elevated in human pancreatic adenocarcinoma. Cancer Epidemiol. Biomarkers Prev. 10, 721–722 (2001).

    CAS  PubMed  Google Scholar 

  111. Ji, B., Bi, Y., Simeone, D., Mortensen, R. M. & Logsdon, C. D. Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin. Gastroenterology 121, 1380–1390 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Shintakuya, R., Uemura, K., Murakami, Y., Kondo, N., Nakagawa, N., Urabe, K. et al. Sarcopenia is closely associated with pancreatic exocrine insufficiency in patients with pancreatic disease. Pancreatology 17, 70–75 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Danai, L. V., Babic, A., Rosenthal, M. H., Dennstedt, E. A., Muir, A., Lien, E. C. et al. Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558, 600–604 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gooden, H. M. & White, K. J. Pancreatic cancer and supportive care—pancreatic exocrine insufficiency negatively impacts on quality of life. Support Care Cancer 21, 1835–1841 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Zuijdgeest-Van Leeuwen, S. D., Van Der Heijden, M. S., Rietveld, T., Van Den Berg, J. W. O., Tilanus, H. W., Burgers, J. A. et al. Fatty acid composition of plasma lipids in patients with pancreatic, lung and oesophageal cancer in comparison with healthy subjects. Clin. Nutr. 21, 225–230 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Matejcic, M., Lesueur, F., Biessy, C., Renault, A. L., Mebirouk, N., Yammine, S. et al. Circulating plasma phospholipid fatty acids and risk of pancreatic cancer in a large European cohort. Int. J. Cancer 143, 2437–2448 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Murphy, R. A., Yeung, E., Mazurak, V. C. & Mourtzakis, M. Influence of eicosapentaenoic acid supplementation on lean body mass in cancer cachexia. Br. J. Cancer 105, 1469–1473 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dewey, A., Baughan, C., Dean, T. P., Higgins, B. & Johnson I. Eicosapentaenoic acid (EPA, an omega‐3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst. Rev. CD004597 (2007)

  119. Haaber, A. B., Rosenfalck, A. M., Hansen, B., Hilsted, J. & Larsen, S. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency. Int. J. Pancreatol. 27, 21–27 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Nakamura, T., Takebe, K., Imamura, K., Tando, Y., Yamada, N., Arai, Y. et al. Fat-soluble vitamins in patients with chronic pancreatitis (pancreatic insufficiency). Acta Gastroenterol. Belg. 59, 10–14 (1996).

    CAS  PubMed  Google Scholar 

  121. Klapdor, S., Richter, E. & Klapdor, R. Vitamin D status and per-oral vitamin D supplementation in patients suffering from chronic pancreatitis and pancreatic cancer disease. Anticancer Res. 32, 1991–1998 (2012).

    CAS  PubMed  Google Scholar 

  122. Dev, R., Del Fabbro, E., Schwartz, G. G., Hui, D., Palla, S. L., Gutierrez, N. et al. Preliminary report: vitamin D deficiency in advanced cancer patients with symptoms of fatigue or anorexia. Oncologist 16, 1637–1641 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Garcia, M., Seelaender, M., Sotiropoulos, A., Coletti, D. & Lancha, A. H. Vitamin D, muscle recovery, sarcopenia, cachexia, and muscle atrophy. Nutrition 60, 66–69 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Camperi, A., Pin, F., Costamagna, D., Penna, F., Menduina, M. L., Aversa, Z. et al. Vitamin D and VDR in cancer cachexia and muscle regeneration. Oncotarget 8, 21778–21793 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Mantovani, G., Madeddu, C. & Maccio, A. Cachexia and oxidative stress in cancer: an innovative therapeutic management. Curr. Pharm. Des. 18, 4813–4818 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Huang, B. Z., Pandol, S. J., Jeon, C. Y., Chari, S. T., Sugar, C. A., Chao, C. R. et al. New-onset diabetes, longitudinal trends in metabolic markers, and risk of pancreatic cancer in a heterogeneous population. J. Gastroenterol. Hepatol. 18, 1812–1821.e7 (2019).

  127. Sah, R. P., Nagpal, S. J. S., Mukhopadhyay, D. & Chari, S. T. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat. Rev. Gastroenterol. Hepatol. 10, 423–433 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Aggarwal, G., Ramachandran, V., Javeed, N., Arumugam, T., Dutta, S., Klee, G. G. et al. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in beta cells and mice. Gastroenterology 143, 1510–1517.e1511 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Armstrong, E. A., Beal, E. W., Chakedis, J., Paredes, A. Z., Moris, D., Pawlik, T. M. et al. Exosomes in Pancreatic Cancer: from Early Detection to Treatment. J. Gastrointest. Surg. 22, 737–750 (2018).

    Article  PubMed  Google Scholar 

  130. Wang, W. S., Liu, X. H., Liu, L. X., Jin, D. Y., Yang, P. Y. & Wang, X. L. Identification of proteins implicated in the development of pancreatic cancer-associated diabetes mellitus by iTRAQ-based quantitative proteomics. J. Proteomics 84, 52–60 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Basso, D., Greco, E., Fogar, P., Pucci, P., Flagiello, A., Baldo, G. et al. Pancreatic cancer-associated diabetes mellitus: an open field for proteomic applications. Clin. Chim. Acta 357, 184–189 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Basso, D., Greco, E., Fogar, P., Pucci, P., Flagiello, A., Baldo, G. et al. Pancreatic cancer-derived S-100A8 N-terminal peptide: a diabetes cause? Clin. Chim. Acta 372, 120–128 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Permert, J., Larsson, J., Westermark, G. T., Herrington, M. K., Christmanson, L., Pour, P. M. et al. Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. N. Engl. J. Med. 330, 313–318 (1994).

    Article  CAS  PubMed  Google Scholar 

  134. Ding, X., Flatt, P. R., Permert, J. & Adrian, T. E. Pancreatic cancer cells selectively stimulate islet β cells to secrete amylin. Gastroenterology 114, 130–138 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. Liu, J., Knezetic, J. A., Strömmer, L., Permert, J., Larsson, J. R. & Adrian, T. E. The intracellular mechanism of insulin resistance in pancreatic cancer patients. J. Clin. Endocrinol. Metab. 85, 1232–1238 (2000).

    CAS  PubMed  Google Scholar 

  136. Yoshikawa, T., Noguchi, Y., Doi, C., Makino, T., Okamoto, T. & Matsumoto, A. Insulin resistance was connected with the alterations of substrate utilization in patients with cancer. Cancer Lett. 141, 93–98 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. Watanapa, P. & Williamson, R. C. Surgical palliation for pancreatic cancer: developments during the past two decades. Br. J. Surg. 79, 8–20 (1992).

    Article  CAS  PubMed  Google Scholar 

  138. Wong, Y. T., Brams, D. M., Munson, L., Sanders, L., Heiss, F., Chase, M. et al. Gastric outlet obstruction secondary to pancreatic cancer: surgical vs endoscopic palliation. Surgical Endosc. 16, 310–312 (2002).

    Article  CAS  Google Scholar 

  139. Dzutsev, A., Badger, J. H., Perez-Chanona, E., Roy, S., Salcedo, R., Smith, C. K. et al. Microbes and cancer. Annu. Rev. Immunol. 35, 199–228 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Torres, P. J., Fletcher, E. M., Gibbons, S. M., Bouvet, M., Doran, K. S. & Kelley, S. T. Characterization of the salivary microbiome in patients with pancreatic cancer. Peer J. 3, e1373 (2015).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  141. Farrell, J. J., Zhang, L., Zhou, H., Chia, D., Elashoff, D., Akin, D. et al. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut 61, 582–588 (2012).

    Article  CAS  PubMed  Google Scholar 

  142. Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Sethi, V., Kurtom, S., Tarique, M., Lavania, S., Malchiodi, Z., Hellmund, L. et al. Gut microbiota promotes tumor growth in mice by modulating immune response. Gastroenterology 155, 33–37 e36 (2018).

    Article  CAS  PubMed  Google Scholar 

  144. Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D. et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Li, S., Fuhler, G. M., Bn, N., Jose, T., Bruno, M. J., Peppelenbosch, M. P. et al. Pancreatic cyst fluid harbors a unique microbiome. Microbiome 5, 147 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Bindels, L. B., Neyrinck, A. M., Loumaye, A., Catry, E., Walgrave, H., Cherbuy, C. et al. Increased gut permeability in cancer cachexia: mechanisms and clinical relevance. Oncotarget 9, 18224–18238 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Pötgens, S. A., Brossel, H., Sboarina, M., Catry, E., Cani, P. D., Neyrinck, A. M. et al. Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction. Sci. Rep. 8, 12321 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Bures, J., Cyrany, J., Kohoutova, D., Forstl, M., Rejchrt, S., Kvetina, J. et al. Small intestinal bacterial overgrowth syndrome. World J. Gastroenterol. 16, 2978–2990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Nishiyama, H., Nagai, T., Kudo, M., Okazaki, Y., Azuma, Y., Watanabe, T. et al. Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice. Biochem. Biophys. Res. Commun. 495, 273–279 (2018).

    Article  CAS  PubMed  Google Scholar 

  150. Varian, B. J., Gourishetti, S., Poutahidis, T., Lakritz, J. R., Levkovich, T., Kwok, C. et al. Beneficial bacteria inhibit cachexia. Oncotarget 7, 11803–11816 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R. et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  CAS  PubMed  Google Scholar 

  152. Ahuja, M., Schwartz, D. M., Tandon, M., Son, A., Zeng, M., Swaim, W. et al. Orai1-mediated antimicrobial secretion from pancreatic acini shapes the gut microbiome and regulates gut innate immunity. Cell Metab. 25, 635–646 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Nay, K., Jollet, M., Goustard, B., Baati, N., Vernus, B., Pontones, M. et al. Gut bacteria are critical for optimal muscle function: a potential link with glucose homeostasis. Am. J. Physiol. Endocrinol. Metab. 317, E158–E171 (2019).

    Article  CAS  PubMed  Google Scholar 

  154. Oliphant, K. & Allen-Vercoe, E. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. Microbiome 7, 91 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Liu, R., Hong, J., Xu, X., Feng, Q., Zhang, D., Gu, Y. et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat. Med. 23, 859–868 (2017).

    Article  CAS  PubMed  Google Scholar 

  156. Biswas, A. K. & Acharyya, S. Understanding cachexia in the context of metastatic progression. Nat. Rev. Cancer 20, 274–284 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Yakovenko, A., Cameron, M. & Trevino, J. G. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J. Gastrointest. Surg. 10, 95–106 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Arends, J., Bachmann, P., Baracos, V., Barthelemy, N., Bertz, H., Bozzetti, F. et al. ESPEN guidelines on nutrition in cancer patients. Clin. Nutr. 36, 11–48 (2017).

    Article  PubMed  Google Scholar 

  159. Shukla, S. K., Gebregiworgis, T., Purohit, V., Chaika, N. V., Gunda, V., Radhakrishnan, P. et al. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab. 2, 18 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  160. May, P. E., Barber, A., D’Olimpio, J. T., Hourihane, A. & Abumrad, N. N. Reversal of cancer-related wasting using oral supplementation with a combination of β-hydroxy-β-methylbutyrate, arginine, and glutamine. Am. J. Surg. 183, 471–479 (2002).

    Article  CAS  PubMed  Google Scholar 

  161. Holecek, M. Side effects of long-term glutamine supplementation. JPEN J. Parenter Enteral. Nutr. 37, 607–616 (2012).

    Article  PubMed  CAS  Google Scholar 

  162. Smith, H. J., Mukerji, P. & Tisdale, M. J. Attenuation of proteasome-induced proteolysis in skeletal muscle by β-hydroxy-β-methylbutyrate in cancer-induced muscle loss. Cancer Res. 65, 277–283 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Wilkinson, D. J., Hossain, T., Hill, D. S., Phillips, B. E., Crossland, H., Williams, J. et al. Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism. J. Physiol. 591, 2911–2923 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Eley Helen, L., Russell Steven, T., Tisdale & Michael, J. Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. Biochem. J. 407, 113–120 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Tayek, J. A., Bistrian, B. R., Hehir, D. J., Martin, R., Moldawer, L. L. & Blackburn, G. L. Improved protein kinetics and albumin synthesis by branched chain amino acid‐enriched total parenteral nutrition in cancer cachexia: a prospective randomized crossover trial. Cancer 58, 147–157 (1986).

    Article  CAS  PubMed  Google Scholar 

  166. Deutz, N. E., Safar, A., Schutzler, S., Memelink, R., Ferrando, A., Spencer, H. et al. Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Clin. Nutr. 30, 759–768 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Berk, L., James, J., Schwartz, A., Hug, E., Mahadevan, A., Samuels, M. et al. A randomized, double-blind, placebo-controlled trial of a beta-hydroxyl beta-methyl butyrate, glutamine, and arginine mixture for the treatment of cancer cachexia (RTOG 0122). Support Care Cancer 16, 1179–1188 (2008).

    Article  PubMed  Google Scholar 

  168. Malta, F. A. P. S., Estadella, D. & Gonçalves, D. C. The role of omega 3 fatty acids in suppressing muscle protein catabolism: a possible therapeutic strategy to reverse cancer cachexia? J. Funct. Foods 54, 1–12 (2019).

    Article  CAS  Google Scholar 

  169. Wigmore, S. J., Barber, M. D., Ross, J. A., Tisdale, M. J. & Fearon, K. C. H. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 36, 177–184 (2000).

    Article  CAS  PubMed  Google Scholar 

  170. Abe, K., Uwagawa, T., Haruki, K., Takano, Y., Onda, S., Sakamoto, T. et al. Effects of ω-3 fatty acid supplementation in patients with bile duct or pancreatic cancer undergoing chemotherapy. Anticancer Res. 38, 2369–2375 (2018).

    CAS  PubMed  Google Scholar 

  171. Fearon, K. C. H., von Meyenfeldt, M. F., Moses, A. G. W., van Geenen, R., Roy, A., Gouma, D. J. et al. Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 52, 1479–1486 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hinson, R. M., Williams, J. A. & Shacter, E. Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2. Proc. Natl Acad. Sci. USA 93, 4885–4890 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Kunkel, S. L., Spengler, M., May, M. A., Spengler, R., Larrick, J. & Remick, D. Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression. J. Biol. Chem. 263, 5380–5384 (1988).

    Article  CAS  PubMed  Google Scholar 

  174. Thompson, M. G., Pascal, M., Mackie, S. C., Thom, A., Morrison, K. S., Colette Backwell, F. R. et al. Evidence that protein kinase C and mitogen activated protein kinase are not involved in the mechanism by which insulin stimulates translation in L6 myoblasts. Biosci. Rep. 15, 37–46 (1995).

    Article  CAS  PubMed  Google Scholar 

  175. Mantovani, G., Maccio, A., Madeddu, C., Serpe, R., Antoni, G., Massa, E. et al. Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia. J. Mol. Med. (Berl) 88, 85–92 (2010).

    Article  CAS  Google Scholar 

  176. Lai, V., George, J., Richey, L., Kim, H. J., Cannon, T., Shores, C. et al. Results of a pilot study of the effects of celecoxib on cancer cachexia in patients with cancer of the head, neck, and gastrointestinal tract. Head Neck 30, 67–74 (2008).

    Article  PubMed  Google Scholar 

  177. McMillan, D. C., Wigmore, S. J., Wigmore, K. C. H., O’Gorman, P., Wright, C. E. & McArdle, C. S. A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss. Br J Cancer 79, 495–500 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. McMillan, D. C., Simpson, J. M., Preston, T., Watson, W. S., Fearon, K. C. H., Shenkin, A. et al. Effect of megestrol acetate on weight loss, body composition and blood screen of gastrointestinal cancer patients. Clin. Nutr. 13, 85–89 (1994).

    Article  CAS  PubMed  Google Scholar 

  179. Gordon, J. N., Trebble, T. M., Ellis, R. D., Duncan, H. D., Johns, T. & Goggin, P. M. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut 54, 540–545 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Wiedenmann, B., Malfertheiner, P., Friess, H., Ritch, P., Arseneau, J., Mantovani, G. et al. A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia. J. Support. Oncol. 6, 18–25 (2008).

    CAS  PubMed  Google Scholar 

  181. Hurwitz, H., Van Cutsem, E., Bendell, J., Hidalgo, M., Li, C.-P., Salvo, M. G. et al. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Invest. New Drugs 36, 683–695 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Solheim, T. S., Laird, B. J. A., Balstad, T. R., Stene, G. B., Bye, A., Johns, N. et al. A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. J. Cachexia Sarcopenia Muscle 8, 778–788 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Solheim, T. S., Laird, B. J., Balstad, T. R., Bye, A., Stene, G., Baracos, V. et al. Cancer cachexia: rationale for the MENAC (Multimodal—Exercise, Nutrition and Anti-inflammatory medication for Cachexia) trial. BMJ Support. Palliat. Care 8, 258–265 (2018).

    Google Scholar 

  184. Wiskemann, J., Clauss, D., Tjaden, C., Hackert, T., Schneider, L., Ulrich, C. M. et al. Progressive resistance training to impact physical fitness and body weight in pancreatic cancer patients: A randomized controlled trial. Pancreas 48, 257–266 (2019).

    Article  PubMed  Google Scholar 

  185. Hamauchi, S., Furuse, J., Takano, T., Munemoto, Y., Furuya, K., Baba, H. et al. A multicenter, open-label, single-arm study of anamorelin (ONO-7643) in advanced gastrointestinal cancer patients with cancer cachexia. Cancer 125, 4294–4302 (2019).

    Article  CAS  PubMed  Google Scholar 

  186. Koch, M., Varela, L., Kim, J. G., Kim, J. D., Hernández-Nuño, F., Simonds, S. E. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Jatoi, A., Windschitl, H. E., Loprinzi, C. L., Sloan, J. A., Dakhil, S. R., Mailliard, J. A. et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J. Clin. Oncol. 20, 567–573 (2002).

    Article  CAS  PubMed  Google Scholar 

  188. Golan, T., Geva, R., Richards, D., Madhusudan, S., Lin, B. K., Wang, H. T. et al. LY2495655, an antimyostatin antibody, in pancreatic cancer: a randomized, phase 2 trial. J. Cachexia Sarcopenia Muscle 9, 871–879 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Riechelmann, R. P., Burman, D., Tannock, I. F., Rodin, G. & Zimmermann, C. Phase II trial of mirtazapine for cancer-related cachexia and anorexia. Am J Hosp. Palliat. Med. 27, 106–110 (2010).

    Google Scholar 

  190. Landers, A., Muircroft, W. & Brown, H. Pancreatic enzyme replacement therapy (PERT) for malabsorption in patients with metastatic pancreatic cancer. BMJ Support. Palliat. Care 6, 75–79 (2016).

    Google Scholar 

  191. Bruno, M., Haverkort, E., Tijssen, G., Tytgat, G., Van & Leeuwen, D. Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region. Gut 42, 92–96 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Dominguez-Munoz, J. E., Nieto-Garcia, L., Lopez-Diaz, J., Larino-Noia, J., Abdulkader, I. & Iglesias-Garcia, J. Impact of the treatment of pancreatic exocrine insufficiency on survival of patients with unresectable pancreatic cancer: a retrospective analysis. BMC Cancer 18, 534 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Woo, S. M., Joo, J., Kim, S. Y., Park, S. J., Han, S. S., Kim, T. H. et al. Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial. Pancreatology 16, 1099–1105 (2016).

    Article  CAS  PubMed  Google Scholar 

  194. Iglesia, D. D. L., Avci, B., Kiriukova, M., Panic, N., Bozhychko, M., Sandru, V. et al. Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: a systematic review and meta-analysis. United European Gastroenterol. J. 8, 1115–1125 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Johnson, C. Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas. Gut 54, v1–v16 (2005).

    Article  CAS  Google Scholar 

  196. Tempero, M. A., Malafa, M. P., Al-Hawary, M., Asbun, H., Bain, A., Behrman, S. W. et al. Pancreatic adenocarcinoma, version 2.2017, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Canc Netw 15, 1028–1061 (2017).

    Article  PubMed  Google Scholar 

  197. Löhr, J. M., Dominguez-Munoz, E., Rosendahl, J., Besselink, M., Mayerle, J., Lerch, M. M. et al. United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol. J. 5, 153–199 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Andersen, D. K., Korc, M., Petersen, G. M., Eibl, G., Li, D., Rickels, M. R. et al. Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66, 1103–1110 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X. M., Braddock, D. T., Albright, R. A. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Oliveira, A. G. & Gomes-Marcondes, M. C. C. Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats. BMC Cancer 16, 418 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Kordes, S., Pollak, M. N., Zwinderman, A. H., Mathôt, R. A., Weterman, M. J., Beeker, A. et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 16, 839–847 (2015).

    Article  CAS  PubMed  Google Scholar 

  202. Chen, S.-M., Chieng, W.-W., Huang, S.-W., Hsu, L.-J. & Jan, M.-S. The synergistic tumor growth-inhibitory effect of probiotic Lactobacillus on transgenic mouse model of pancreatic cancer treated with gemcitabine. Sci. Rep. 10, 20319 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Riquelme, E., Zhang, Y., Zhang, L., Montiel, M., Zoltan, M., Dong, W. et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 178, 795–806.e712 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Cheng, W. Y., Wu, C.-Y. & Yu, J. The role of gut microbiota in cancer treatment: friend or foe? Gut 69, 1867–1876 (2020).

    Article  CAS  PubMed  Google Scholar 

  205. Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  206. Aguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Talbert, E. E., Cuitiño, M. C., Ladner, K. J., Rajasekerea, P. V., Siebert, M., Shakya, R. et al. Modeling human cancer-induced cachexia. Cell Rep. 28, 1612–1622.e1614 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Henderson, S. E., Makhijani, N. & Mace, T. A. Pancreatic cancer–induced cachexia and relevant mouse models. Pancreas 47, 937–945 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Rainer Heuchel for his critical comments and Erika Nieser for language editing.

Author information

Authors and Affiliations

  1. Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden

    Maximilian Kordes & J.-Matthias Löhr

  2. Department of Upper Abdominal Diseases, Cancer Theme, Karolinska University Hospital, Stockholm, Sweden

    Maximilian Kordes & J.-Matthias Löhr

  3. Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

    Lars Larsson

  4. Department of Clinical Genetics, Science for Life Laboratory, Stockholm, Sweden

    Lars Engstrand

Authors
  1. Maximilian Kordes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lars Larsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lars Engstrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J.-Matthias Löhr
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: M.K. and J.M.L. Manuscript writing: M.K. and J.M.L. Final approval of manuscript: all authors. Accountable for all aspects of the work: all authors.

Corresponding author

Correspondence to J.-Matthias Löhr.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Data availability

Not applicable.

Competing interests

M.K.: Alligator Bioscience (Consulting), Roche (Consulting); L.L.: no disclosures; L.E.: no disclosures; J.M.L.: Abbot (Honoraria), Mylan (Honoraria).

Funding information

This work was supported through a clinician-scientist grant from Region Stockholm to M.K. and the Lars Vesterlund minnesfond to J.M.L.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kordes, M., Larsson, L., Engstrand, L. et al. Pancreatic cancer cachexia: three dimensions of a complex syndrome. Br J Cancer 124, 1623–1636 (2021). https://doi.org/10.1038/s41416-021-01301-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01301-4

This article is cited by

Search

Advanced search

Quick links