Using space-based investigations to inform cancer research on Earth

Key Points

  • In the microgravity environment of space, cells assemble into multicellular three-dimensional constructs.

  • Reduced gravitational force has been shown to have far-ranging effects on cell growth and function, including effects on gene expression, the production of soluble factors, cell signalling and cytoskeletal organization.

  • Suspension-based cell culture can be achieved using the rotating wall bioreactor, clinostat, random positioning machine and magnetic levitation. These models provide certain conditions that are observed during culture in microgravity, including lack of sedimentation, reduced fluid shear, optimized cellular colocation and three-dimensional growth.

  • Research approaches derived from space-based investigations may be applicable to advance our knowledge of tumour biology, as well as inform the development of new anticancer technologies and therapeutic strategies.

Abstract

Experiments conducted in the microgravity environment of space are not typically at the forefront of the mind of a cancer biologist. However, space provides physical conditions that are not achievable on Earth, as well as conditions that can be exploited to study mechanisms and pathways that control cell growth and function. Over the past four decades, studies have shown how exposure to microgravity alters biological processes that may be relevant to cancer. In this Review, we explore the influence of microgravity on cell biology, focusing on tumour cells grown in space together with work carried out using models in ground-based investigations.

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Figure 1: RWV bioreactor 3D cell culture.
Figure 2: The RPM.
Figure 3: Magnetic levitation 3D cell culture.
Figure 4: 3D tumour cell aggregates.
Figure 5: Culture of LN1 human mixed mullerian ovarian tumour cells aboard the ISS.

References

  1. 1

    van Loon, J. J. W. A. in Biology in Space and Life on Earth. Effects of Spaceflight on Biological Systems (ed. Brinckmann, E.) 17–32 (Wiley-VCH, 2007).

    Google Scholar 

  2. 2

    NASA. What is Microgravity? [online], (2013).

  3. 3

    Unsworth, B. R. & Lelkes, P. I. Growing tissues in microgravity. Nature Med. 4, 901–907 (1998).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Todd, P. Gravity-dependent phenomena at the scale of the single cell. ASGSB Bull. 2, 95–113 (1989).

    CAS  PubMed  Google Scholar 

  5. 5

    Hammond, T. G. & Hammond, J. M. Optimized suspension culture: the rotating-wall vessel. Am. J. Physiol. Renal Physiol. 281, F12–F25 (2001). This paper reviews the engineering principles of suspension culture and presents mechanisms for the changes in the properties of cells cultured in suspension; the operating parameters for the RWV culture system are also detailed in this review.

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Freed, L. E., Langer, R., Martin, I., Pellis, N. R. & Vunjak-Novakovic, G. Tissue engineering of cartilage in space. Proc. Natl Acad. Sci. USA 94, 13885–13990 (1997).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Montgomery, P. O. et al. in Biomedical Results from Skylab (eds Johnson, R. S. & Dietlein, L. F.) 221–234 (Scientific and Technical Information Office, 1977).

    Google Scholar 

  8. 8

    Montgomery, P. O. et al. The response of single human cells to zero-gravity. In Vitro 14, 165–173 (1978).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Kimzey, S. L., Ritzmann, S. E., Mengel, C. E. & Fischer, C. L. Skylab experiment results: hematology studies. Acta Astronaut. 2, 141–154 (1975).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Kimzey, S. L. in Biomedical Results from Skylab ( eds Johnson, R. S. & Dietlein, L. F. ) 249–282 (Scientific and Technical Information Office, 1977).

    Google Scholar 

  11. 11

    Cogoli, A. Hematological and immunological changes during spaceflight. Acta Astronaut. 8, 995–1002 (1981).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Cogoli, A. Space flight and the immune system. Vaccine 11, 496–503 (1993).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Bilodeau, K. & Mantovani, D. Bioreactors for tissue engineering: focus on mechanical constraints. A comparative review. Tissue Eng. 12, 2367–2383 (2006).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Souza, G. R. et al. Three-dimensional tissue culture based on magnetic cell levitation. Nature Nanotechnol. 5, 291–296 (2010). This paper presents the operating parameters for magnetic levitation cell culture.

    CAS  Article  Google Scholar 

  15. 15

    Emerman, J. T. & Pitelka, D. R. Maintenance and induction of morphological differentiation in dissociated mammary epithelium on floating collagen membranes. In Vitro 13, 316–328 (1977).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Lee, E. Y., Lee, W. H., Kaetzel, C. S., Parry, G. & Bissell, M. J. Interaction of mouse mammary epithelial cells with collagen substrata: regulation of casein gene expression and secretion. Proc. Natl Acad. Sci. USA 82, 1419–1423 (1985).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Petersen, O. W., Ronnov-Jessen, L., Howlett, A. R. & Bissell, M. J. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc. Natl Acad. Sci. USA 89, 9064–9068 (1992).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Lee, G. Y., Kenny, P. A., Lee, E. H. & Bissell, M. J. Three-dimensional culture models of normal and malignant breast epithelial cells. Nature Methods 4, 359–365 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Nelson, C. M. & Bissell, M. J. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Ann. Rev. Cell Dev. Biol. 22, 287–309 (2006).

    CAS  Article  Google Scholar 

  20. 20

    Debnath, J., Muthuswamy, S. K. & Brugge, J. S. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30, 256–268 (2003).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Nederman, T., Norling, B., Glimelius, B., Carlsson, J. & Brunk, U. Demonstration of an extracellular matrix in multicellular tumor spheroids. Cancer Res. 44, 3090–3097 (1984).

    CAS  PubMed  Google Scholar 

  22. 22

    Nederman, T. Effects of vinblastine and 5-fluorouracil on human glioma and thyroid cancer cell monolayers and spheroids. Cancer Res. 44, 254–258 (1984).

    CAS  PubMed  Google Scholar 

  23. 23

    Acker, H., Carlsson, J., Holtermann, G., Nederman, T. & Nylen, T. Influence of glucose and buffer capacity in the culture medium on growth and pH in spheroids of human thyroid carcinoma and human glioma origin. Cancer Res. 47, 3504–3508 (1987).

    CAS  PubMed  Google Scholar 

  24. 24

    Carlsson, J. & Nederman, T. A method to measure the radio and chemosensitivity of human spheroids. Adv. Exp. Med. Biol. 159, 399–417 (1983).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Acker, H., Holtermann, G., Bolling, B. & Carlsson, J. Influence of glucose on metabolism and growth of rat glioma cells (C6) in multicellular spheroid culture. Int. J. Cancer 52, 279–285 (1992).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Acker, H. The use of human tumor cells grown in multicellular spheroid culture for designing and improving therapeutic strategies. J. Theor. Med. 1, 193–207 (1998).

    Article  Google Scholar 

  27. 27

    Kunz-Schughart, L. A., Kreutz, M. & Kneuchel, R. Multicellular spheroids: a three-dimensional in vitro culture system to study tumour biology. Int. J. Exp. Path. 79, 1–23 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Tsao, Y. D., Goodwin, T. J., Wolf, D. A. & Spaulding, G. F. Responses of gravity level variations on the NASA/JSC bioreactor system. Physiologist 35, S49–S50 (1992).

    CAS  PubMed  Google Scholar 

  29. 29

    Schwarz, R. P., Goodwin, T. J. & Wolf, D. A. Cell culture for three-dimensional modeling in rotating-wall vessels: an application of simulated microgravity. J. Tiss. Cult. Meth. 14, 51–57 (1992).

    CAS  Article  Google Scholar 

  30. 30

    Jessup, J. M., Goodwin, T. J. & Spaulding, G. F. Prospects for use of microgravity-based bioreactors to study three-dimensional host-tumor interactions in human neoplasia. J. Cell. Biochem. 51, 290–300 (1993).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Goodwin, T. J., Prewett, T. L., Wolf, D. A. & Spaulding, G. F. Reduced shear stress: a major component in the ability of mammalian tissues to form three-dimensional assemblies in simulated microgravity. J. Cell Biochem. 51, 301–311 (1993).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Klaus, D. M. Clinostats and bioreactors. Grav. Space Biol. Bull. 14, 55–64 (2001). This paper presents the engineering principles and operating parameters for clinorotation.

    CAS  Google Scholar 

  33. 33

    Mazzoleni, G., Di Lorenzo, D. & Steimberg, N. Modeling tissues in 3D: the next future of pharmaco-toxicology and food research? Genes Nutr. 4, 13–22 (2009).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Briegleb, W. Some qualitative and quantitative aspects of the fast-rotating clinostat as a research tool. ASGSB Bull. 5, 23–30 (1992).

    CAS  PubMed  Google Scholar 

  35. 35

    Kessler, J. O. The internal dynamics of slowly rotating biological systems. ASGSB Bull. 5, 11–21 (1992).

    CAS  PubMed  Google Scholar 

  36. 36

    Becker, J. L. & Blanchard, D. K. Characterization of primary breast carcinomas grown in three-dimensional cultures. J. Surg. Res. 142, 256–262 (2007).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Kaur, P. et al. Human breast cancer histoid: an in vitro 3-dimensional co-culture model that mimics breast cancer tissue. J. Histochem. Cytochem. 59, 1087–1100 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Vamvakidou, A. P. et al. Heterogeneous breast tumoroids: an in vitro assay for investigating cellular heterogeneity and drug delivery. J. Biomol. Screen. 12, 13–20 (2007).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Chopra, V., Dinh, T. V. & Hannigan, E. V. Three-dimensional endothelial-tumor epithelial cell interactions in human cervical cancer. In Vitro Cell. Dev. Biol. Anim. 33, 432–442 (1997).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Goodwin, T. J., Jessup, J. M. & Wolf, D. A. Morphologic differentiation of colon carcinoma cell lines HT-29 and HT-29KM in rotating-wall vessels. In Vitro Cell. Dev. Biol. Anim. 28, 47–60 (1992).

    Article  Google Scholar 

  41. 41

    Jessup, J. M. et al. Induction of carcinoembryonic antigen expression in a three-dimensional culture system. In Vitro Cell. Dev. Biol. Anim. 33, 352–357 (1997).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Jessup, J. M. et al. Microgravity culture reduces apoptosis and increases the differentiation of a human colorectal carcinoma cell line. In Vitro Cell. Dev. Biol. Anim. 36, 367–373 (2000).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Chang, T. T. & Hughes-Fulford, M. Monolayer and spheroid culture of human liver hepatocellular carcinoma cell line cells demonstrate distinct global gene expression patterns and functional phenotypes. Tissue Eng. Part A 15, 559–567 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Tang, J. et al. A three dimensional cell biology model of human hepatocellular carcinoma in vitro. Tumour Biol. 32, 469–479 (2011).

    PubMed  Article  Google Scholar 

  45. 45

    Redden, R. A. & Doolin, E. J. Microgravity assay of neuroblastoma: in vitro aggregation kinetics and organoid morphology correlate with MYCN expression. In Vitro Cell. Dev. Biol. Anim. 47, 312–317 (2011).

    PubMed  Article  Google Scholar 

  46. 46

    Taga, M. et al. Melanoma growth and tumorigenicity in models of microgravity. Aviat. Space Environ. Med. 77, 1113–1116 (2006).

    PubMed  Google Scholar 

  47. 47

    Marrero, B., Messina, J. L. & Heller, R. Generation of a tumor spheroid in a microgravity environment as a 3D model of melanoma. In Vitro Cell. Dev. Biol. Anim. 45, 523–534 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Licato, L. L., Prieto, V. G. & Grimm, E. A. A novel preclinical model of human malignant melanoma utilizing bioreactor rotating-wall vessels. In Vitro Cell. Dev. Biol. Anim. 37, 121–126 (2001).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Becker, J. L., Prewett, T. L., Spaulding, G. F. & Goodwin, T. J. Three-dimensional growth and differentiation of ovarian tumor cell line in high aspect rotating wall vessel: morphologic and embryologic considerations. J. Cell. Biochem. 51, 283–289 (1993).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Goodwin, T. J., Prewett, T. L., Spaulding, G. F. & Becker, J. L. Three-dimensional culture of a mixed mullerian tumor of the ovary: expression of in vivo characteristics. In Vitro Cell. Dev. Biol. Anim. 33, 366–374 (1997).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Zhau, H. E., Goodwin, T. J., Chang, S. M., Baker, T. L. & Chung, L. W. Establishment of a three-dimensional human prostate organoid coculture under microgravity-simulated conditions: evaluation of androgen induced growth and PSA expression. In Vitro Cell. Dev. Biol. Anim. 33, 375–380 (1997).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Ingram, M. et al. Three-dimensional growth of various human tumor cell lines in simulated microgravity of a NASA bioreactor. In Vitro Cell. Dev. Biol. Anim. 33, 459–466 (1997).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Wang, R. et al. Three-dimensional co-culture models to study prostate cancer growth, progression and metastasis to bone. Semin. Cancer Biol. 15, 353–364 (2005).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Sung, S. Y. et al. Coevolution of prostate cancer and bone stroma in three-dimensional coculture: implications for cancer growth and metastasis. Cancer Res. 68, 9996–10003 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Clejan, S., O'Connor, K. & Rosensweig, N. Tri-dimensional prostate cell cultures in simulated microgravity and induced changes in lipid second messengers and signal transduction. J. Cell. Mol. Med. 5, 60–73 (2001).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Matsuoka, R., Ohkubo, S., Yoshida, M. & Nakahata, N. Alteration of adenylyl cyclase type 6 expression in human astrocytoma cells after exposure to simulated microgravity. J. Health Sci. 53, 534–542 (2007).

    CAS  Article  Google Scholar 

  57. 57

    Rijken, P. J. et al. Epidermal growth factor-induced cell rounding is sensitive to simulated microgravity. Aviat. Space Environ. Med. 62, 32–36 (1991).

    CAS  PubMed  Google Scholar 

  58. 58

    Rijken, P. J. et al. Altered gravity conditions affect early EGF-induced signal transduction in human epidermal A431 cells. ASGSB Bull. 5, 77–82 (1992).

    CAS  PubMed  Google Scholar 

  59. 59

    Rijken, P. J. et al. Identification of specific gravity sensitive signal transduction pathways in human A431 carcinoma cells. Adv. Space Res. 12, 145–152 (1992).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Kaneko, T. et al. Simulated conditions of microgravity increase progesterone production in I-10 Leydig tumor cell line. Int. J. Urol. 15, 245–250 (2008).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Ivanova, K. et al. Natriuretic peptide-sensitive guanylyl cyclase expression is down-regulated in human melanoma cells at simulated weightless. Acta Astronaut. 68, 652–655 (2011).

    CAS  Article  Google Scholar 

  62. 62

    Qu, L. et al. Protective effects of flavonoids against oxidative stress induced by simulated microgravity in SH-SY5Y cells. Neurochem. Res. 35, 1445–1454 (2010).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Granet, C., Boutahar, N., Vico, L., Alexandre, C. & Lafage-Proust, M. H. MAPK and SRC-kinases control EGR-1 and NF-kappa B inductions by changes in mechanical environment in osteoblasts. Biochem. Biophys. Res. Commun. 284, 622–631 (2001).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Kobayashi, K. et al. TNF-alpha-dependent activation of NF-kappa B in human osteoblastic HOS-TE85 cells is repressed in vector-averaged gravity using clinostat rotation. Biochem. Biophys. Res. Commun. 279, 2258–2264 (2000).

    Article  CAS  Google Scholar 

  65. 65

    Sarkar, D., Nagaya, T., Koga, K. & Seo, H. Culture in vector-averaged gravity environment in a clinostat results in detachment of osteoblastic ROS 17/2.8 cells. Environ. Med. 43, 22–24 (1999).

    CAS  PubMed  Google Scholar 

  66. 66

    Grimm D. et al. Effects of simulated microgravity on thyroid carcinoma cells. J. Gravit. Physiol. 9, 39–42 (2002).

    Google Scholar 

  67. 67

    Grimm, D. et al. Simulated microgravity alters differentiation and increases apoptosis in human follicular thyroid carcinoma cells. FASEB J. 16, 604–606 (2002).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Kossmehl, P. et al. Weightlessness induced apoptosis in normal thyroid cells and papillary thyroid carcinoma cells via extrinsic and intrinsic pathways. Endocrinol. 144, 4172–4179 (2003).

    CAS  Article  Google Scholar 

  69. 69

    Infanger, M. et al. Long-term conditions of mickmicked weightlessness influences the cytoskeleton in thyroid cells. J. Gravit. Physiol. 11, 169–172 (2004).

    Google Scholar 

  70. 70

    Infanger, M. et al. Simulated weightless changes the cytoskeleton and extracellular matrix proteins in papillary thyroid carcinoma cells. Cell Tissue Res. 324, 267–277 (2006).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Grosse, J. et al. Gravity-sensitive signaling drives 3-dimensional formation of multicellular thyroid cancer spheroids. FASEB J. 26, 5124–5140 (2012).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Borst, A. G. & van Loon, J. J.W. A. Technology and developments for the random positioning machine, RPM. Micrograv. Sci. Technol. 21, 287–292 (2007). This paper presents the engineering principles and operating parameters for the RPM.

    Article  Google Scholar 

  73. 73

    Leguy, C. A. D. et al. Fluid motion for microgravity simulations in a random positioning machine. Grav. Space Biol. 25, 36–39 (2011).

    Google Scholar 

  74. 74

    Huijser, R. H. Desktop RPM: new small size microgravity simulator for the bioscience laboratory. [online], (2000).

  75. 75

    Pardo, S. J. et al. Simulated microgravity using the random positioning machine inhibits differentiation and alters gene expression of 2T3 preosteoblasts. Am. J. Physiol. Cell Physiol. 288, C1211–C1221 (2005).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Takeda, M. et al. Effects of simulated microgravity on proliferation and chemosensitivity in malignant glioma cells. Neurosci. Lett. 463, 54–59 (2009).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Monici, M. et al. Modeled gravitational unloading triggers differentiation and apoptosis in preosteoblastic cells. J. Cell. Biochem. 98, 65–80 (2006).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Cuccarolo, P., Barbieri, F. Sancandi, M. Viaggi, S. & Degan, P. Differential behaviour of normal, transformed and Fanconi's anemia lymphoblastoid cells to modeled microgravity. J. Biomed. Sci. 17, 63–72 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79

    Han, J. et al. Molecular predictors of 3D morphogenesis by breast cancer cell lines in 3D culture. PLoS Computational Biology 6, e1000684 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80

    Kim, J. B., Stein, R. & O'Hare, M. J. Three-dimensional in vitro tissue culture models of breast cancer – a review. Breast Cancer Res. Treat. 85, 281–291 (2004).

    PubMed  Article  Google Scholar 

  81. 81

    Griffith, L. G. & Swartz, M. A. Capturing complex 3D tissue physiology in vitro. Nature Rev. Mol. Cell. Biol. 7, 211–224 (2006).

    CAS  Article  Google Scholar 

  82. 82

    Boudreau, N. & Weaver, V. Forcing the Third Dimension. Cell 125, 429–431 (2006).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Lee, J., Cuddihy, M. J. & Kotov, N. A. Three-dimensional cell culture matrices: state of the art. Tissue Eng. Part B Rev. 14, 61–86 (2008).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Molina, J., Hayashi, Y., Stephens, C. & Georgescu, M. M. Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia 12, 453–463 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Lee, J. S., Morrisett, J. D. & Tung, C. H. Detection of hydroxyapatite in calcified cardiovascular tissues. Atheroscler. 224, 3340–3347 (2012).

    Google Scholar 

  86. 86

    Valles, J. M., Lin, K., Denegre, J. M. & Mowry, K. L. Stable magnetic field gradient levitation of Xenopus laevis: toward low gravity simulation. Biophys. J. 73, 1130–1133 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Valles, J. M. & Guevorkian, L. K. Low gravity on earth by magnetic levitation of biological material. J. Gravit. Physiol. 9, 7–10 (2002).

    Google Scholar 

  88. 88

    Coleman, C. B. et al. Diamagnetic levitation changes growth, cell cycle, and gene expression of Saccharomyces cerevisiae. Biotechnol. Bioeng. 98, 854–863 (2007).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Valles, J. M., Maris, H. J. Seidel, G. M., Tang, J. & Yao, W. Magnetic levitation-based Martian and Lunar gravity simulator. Adv. Space Res. 36, 114–118 (2005).

    PubMed  Article  Google Scholar 

  90. 90

    Daquinag, A. C., Souza, G. R. & Kolonin, M. G. Adipose tissue engineering in three-dimensional levitation culture system based on magnetic nanoparticles. Tiss. Engr. Part C Meth. 19, 336–344 (2013).

    CAS  Article  Google Scholar 

  91. 91

    Tseng, H. et al. Assembly of a three-dimensional multitype bronchiole co-culture model using magnetic levitation. Tiss. Eng. Part C Methods 25 Feb 2013 (doi:10.1089/ten.TEC.2012.0157).

  92. 92

    Chitocholtan, K., Sykes, P. H. & Evans, J. J. The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer. J. Transl. Med. 10, 38 (2012).

    Article  CAS  Google Scholar 

  93. 93

    Hammer, B. E., Kidder, L. S., Williams, P. C. & Xu, W. W. Magnetic levitation of MC3T3 osteoblast cells as a ground based simulation of microgravity. Micrograv. Sci. Technol. 21, 311–318 (2009).

    CAS  Article  Google Scholar 

  94. 94

    Qian, A. R. et al. Large gradient high magnetic field affects the association of MACF-1 with actin and microtubule cytoskeleton. Bioelectromag. 30, 545–555 (2009).

    CAS  Article  Google Scholar 

  95. 95

    Lawler, K., Foran, E., O'Sullivan, G., Long, A. & Kenny, D. Mobility and invasiveness of metastatic esophageal cancer are potentiated by shear stress in a ROCK- and Ras-dependent manner. Am. J. Physiol. Cell Physiol. 291, C668–C677 (2006).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Lawler, K., O'Sullivan, G., Long, A. & Kenny, D. Shear stress induces internalization of E-cadherin and invasiveness in metastatic oesophageal cancer cells by a Src-dependent pathway. Cancer Sci. 100, 1082–1087 (2009).

    CAS  Article  PubMed  Google Scholar 

  97. 97

    Liang, S., Hoskins, M., Khanna, P., Kunz, R. F. & Dong, C. Effects of tumor-leukocyte environment on melanoma – neutrophil adhesion to the endothelium in a shear flow. Cell. Mol. Bioeng. 1, 189–200 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Michor, F., Liphardt, J., Ferrari, M. & Widom, J. What does physics have to do with cancer? Nature Rev. Cancer 11, 657–670 (2011).

    CAS  Article  Google Scholar 

  99. 99

    Wirtz, D., Konstantopoulos, K. & Searson, P. C. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nature Rev. Cancer 11, 512–522 (2011). This paper reviews key elements of the effect of physical forces on cancer cell metastasis in the context of a 3D configuration.

    CAS  Article  Google Scholar 

  100. 100

    Kim, Y. J. et al. Overcoming evasive resistance from vascular endothelial growth factor A inhibition in sarcomas by genetic or pharmacologic targeting of hypoxia-inducing factor 1 alpha. Int. J. Cancer 132, 29–41 (2013).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Murat, A. et al. Modulation of angiogenic and inflammatory response in glioblastoma by hypoxia. PLoS ONE 4, e5947 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102

    Talbot, L. J., Bhattacharya, S. D. & Kuo, P. C. Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int. J. Biochem. 3, 117–136 (2012).

    CAS  Google Scholar 

  103. 103

    Roberts, D. L. et al. Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells. Br. J. Cancer 101, 1290–1297 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104

    Dufau, I. et al. Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer. BMC Cancer 13 Jan 2012 (doi:10.1186/1471-2407).

  105. 105

    Kobayashi, H. et al. Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc. Natl Acad. Sci. USA 90, 3294–3298 (1993).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Graham, C. H. et al. Rapid acquisition of multicellular drug resistance after a single exposure of mammary tumor cells to antitumor alkylating agents. J. Natl Cancer Inst. 86, 975–982 (1994).

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Kerbel, R. S., St. Croix, B., Florenes, V. A. & Rak, J. Induction and reversal of cell adhesion-dependent multicellular drug resistance in solid breast tumors. Hum. Cell 9, 257–264 (1996).

    CAS  PubMed  Google Scholar 

  108. 108

    Desoize, B. & Jardillier, J. C. Multicellular resistance: a paradigm for clinical resistance? Crit. Rev. Oncol. Hematol. 36, 193–207 (2000).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Sonnenfeld, G. et al. Spaceflight alters immune cell function and distribution. J. Appl. Physiol. 73, 191S–195S (1992).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Lesnyak, A. T. et al. Immune changes in test animals during spaceflight. J. Leuk. Biol. 54, 214–226 (1993).

    CAS  Article  Google Scholar 

  111. 111

    Sonnenfeld, G. et al. Spaceflight and development of immune responses. J. Appl. Physiol. 85, 1429–1433 (1998).

    CAS  PubMed  Article  Google Scholar 

  112. 112

    Taylor, G. R., Kostantinova, I., Sonnenfeld, G. & Jennings, R. Changes in the immune system during and after spaceflight. Adv. Space Biol. Med. 6, 1–32 (1997).

    CAS  PubMed  Article  Google Scholar 

  113. 113

    Gridley, D. S. et al. Spaceflight effects on T lymphocyte distribution, function and gene expression. J. Appl. Physiol. 106, 194–202 (2009). This paper presents microgravity-induced effects on T cells, as well as on the expression of cancer-associated genes, and also reviews earlier studies on the effects of reduced gravity exposure on the immune system.

    PubMed  Article  Google Scholar 

  114. 114

    Chapes, S. K., Morrison, D. R., Guikema, J. A., Lewis, M. L. & Spooner, B. S. Cytokine secretion by immune cells in space. J. Leuk. Biol. 52, 104–110 (1992).

    CAS  Article  Google Scholar 

  115. 115

    Miller, E. S., Koebel, D. A. & Sonnenfeld, G. A. Influence of spaceflight on the production of interleukin-3 and interleukin-6 by rat spleen and thymus cells. J. Appl. Physiol. 78, 810–813 (1995).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Reynolds, R. J. & Day, S. M. Mortality among US astronauts: 1980–2009. Aviat. Space Environ. Med. 81, 1024–1027 (2010).

    PubMed  Article  Google Scholar 

  117. 117

    Longnecker, D. E., Manning, F. J. & Worth, M. H. (eds) in Review of NASA's Longitudinal Study of Astronaut Health 24–25 (Institute of Medicine of the National Academies, 2004).

    Google Scholar 

  118. 118

    Hammond, T. G. et al. Gene expression in space. Nature Med. 5, 359 (1999).

    CAS  PubMed  Article  Google Scholar 

  119. 119

    Hammond, T. G. et al. Mechanical culture conditions affect gene expression: gravity-induced changes on the space shuttle. Physiol. Genom. 8, 163–173 (2000). This paper details the first demonstration of microgravity exposure to elicit broad modulation of cellular gene expression.

    Article  Google Scholar 

  120. 120

    Lewis, M. L. et al. cDNA microarray reveals altered cytoskeletal expression in space-flown leukemic T lymphocytes (Jurkat). FASEB J. 15, 1783–1805 (2001). This paper details the first demonstration of microgravity-induced alterations of global gene expression in Jurkat cells and provides insight into potential mechanisms underlying cellular cytoskeletal disruption occurring in space.

    CAS  PubMed  Article  Google Scholar 

  121. 121

    Lewis, M. L. et al. Spaceflight alters microtubules and increases apoptosis in human lymphocytes (Jurkat). FASEB J. 12, 1007–1018 (1998).

    CAS  PubMed  Article  Google Scholar 

  122. 122

    Zhang, Z. J. et al. Spaceflight alters the gene expression profile of cervical cancer cells. Chin. J. Cancer 30, 842–852 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123

    Guo, F. et al. Identification of genes associated with tumor development in CaSki cells in the cosmic space. Mol. Biol. Rep. 39, 6923–6931 (2012).

    CAS  PubMed  Article  Google Scholar 

  124. 124

    Bausch, D. et al. Plectin-1 as a novel biomarker for pancreatic cancer. Clin. Cancer Res. 17, 302–309 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125

    Svitkina, T. M., Verkhovsky, A. B. & Borisy, G. B. Plectin sidearms mediate interactions of intermediate filaments with microtubules and other components of the cytoskeleton. J. Cell Biol. 135, 991–1007 (1996).

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Katada, K. et al. Plectin promotes migration and invasion of cancer cells and is a novel prognostic marker for head and neck squamous cell carcinoma. J. Proteom. 75, 1803–1815 (2012).

    CAS  Article  Google Scholar 

  127. 127

    McInroy, L. & Maatta, A. Plectin regulates invasiveness of SW480 colon carcinoma cells and is targeted to podosome-like adhesions in an isoform-specific manner. Exp. Cell Res. 317, 2468–2478 (2011).

    CAS  PubMed  Article  Google Scholar 

  128. 128

    Schmitt, D. A. et al. The distribution of protein kinase C in human leukocytes is altered in microgravity. FASEB J. 10, 1627–1634 (1996).

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Hatton, J. P. et al. The kinetics of translocation and cellular quantity of protein kinase C in human leukocytes are modified during spaceflight. FASEB J. 13, S23–S33 (1999).

    CAS  PubMed  Article  Google Scholar 

  130. 130

    Hatton, J. P., Gaubert, F., Cazenave, J. P. & Schmitt, D. Microgravity modifies protein kinase C isoform translocation in the human monocytic cell line U937 and human peripheral blood T cells. J. Cell. Biochem. 87, 39–50 (2002).

    CAS  PubMed  Article  Google Scholar 

  131. 131

    Carmeliet, G., Nys, G. & Bouillon, R. Microgravity reduces the differentiation of human osteoblastic MG-63 cells. J. Bone Min. Res. 12, 786–794 (1997).

    CAS  Article  Google Scholar 

  132. 132

    Piepmeier, E. H., Kalns, J. E., McIntyre, K. M. & Lewis, M. L. Prolonged weightlessness affects promyelocytic multidrug resistance. Exp. Cell Res. 237, 410–418 (1997).

    CAS  PubMed  Article  Google Scholar 

  133. 133

    Vassy, J . et al. The effect of weightlessness on cytoskeletal architecture and proliferation of human breast cancer cell line MCF-7. FASEB J. 15, 1104–1106 (2001).

    CAS  PubMed  Article  Google Scholar 

  134. 134

    Wagner, H. E. et al. Characterization of the tumorigenic and metastatic potential of a poorly differentiated human colon carcinoma cell line. Invasion Met. 10, 253–266 (1990).

    CAS  Google Scholar 

  135. 135

    Hammond, D. K. et al. Antigenic protein in microgravity-grown human mixed mullerian ovarian tumor (LN1) cells preserved in RNA stabilizing agent. Grav. Space Biol. 18, 99–100 (2005).

    CAS  Google Scholar 

  136. 136

    Wang, Y. et al. Regulatory effect of E2, IL-6 and IL-8 on the growth of epithelial ovarian cancer cells. Cell. Mol. Immunol. 2, 365–372 (2005).

    CAS  PubMed  Google Scholar 

  137. 137

    Duan, Z., Feller, A. J., Penson, R. T., Chabner, B. A. & Seiden, M. V. Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8 and monocyte chemotactic protein 1 in the paclitaxel resistant phenotype. Clin. Cancer Res. 5, 3445–3553 (1999).

    CAS  PubMed  Google Scholar 

  138. 138

    Wang, Y. et al. Reciprocal regulation of 5 alpha-dihydrotesterone, interleukin-6 and interleukin-8 during proliferation of epithelial ovarian carcinoma. Cancer Biol. Therap. 6, 864–871 (2007).

    CAS  Article  Google Scholar 

  139. 139

    Yin, Y., Si, X., Gao, Y., Gao, L. & Wang, J. The nuclear factor-κB correlates with increased expression of interleukin-6 and promotes progression of gastric carcinoma. Oncol. Rep. 29, 34–38 (2013).

    CAS  PubMed  Article  Google Scholar 

  140. 140

    Tran, H. et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanid for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 13, 827–837 (2012).

    CAS  PubMed  Article  Google Scholar 

  141. 141

    Shi, Z. et al. Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8. Breast Cancer Res. Treat. 135, 737–747 (2012).

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Becker, J. L., Papenhausen, P. R. & Widen, R. H. Cytogenetic, morphologic and oncogene analysis of cell line derived from heterologous mixed mullerian tumor of the ovary. In Vitro Cell. Dev. Biol. Anim. 33, 325–331 (1997).

    CAS  PubMed  Article  Google Scholar 

  143. 143

    Twombly, R. Prostate modeling experiment success becomes part of legacy of shuttle astronauts. J. Natl Cancer Inst. 95, 505–507 (2003).

    PubMed  Article  Google Scholar 

  144. 144

    Chong, H. C., Tan, C. K., Huang, R. & Tan, N. S. Matricellular proteins: a sticky affair with cancers. J. Oncol. 9 Feb 2012 (doi:10.1155/2012/351089).

  145. 145

    Midwood, K. S., Hussenet, T., Langlois, B. & Orend, G. Advances in tenascin-c biology. Cell. Mol. Life Sci. 68, 3175–3199 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146

    Lewis, M. L. The cytoskeleton in spaceflown cells: an overview. Grav. Space Biol. Bull. 17, 1–11 (2004). This paper reviews key concepts and mechanisms regarding cell shape changes and associated cytoskeletal alterations induced by microgravity exposure.

    Google Scholar 

  147. 147

    Tabony, J. Gravity dependence of microtubule self-organization. Grav. Space Biol. Bull. 17, 13–25 (2004). This paper describes the influence of spatial configuration and gravity on microtubule reaction-diffusion processes.

    Google Scholar 

  148. 148

    Papaseit, C., Pochon, N. & Tabony, J. Microtubule self-organization is gravity-dependent. Proc. Natl Acad. Sci. USA 97, 8364–8368 (2000).

    CAS  PubMed  Article  Google Scholar 

  149. 149

    Glade, N., Beaugnon, E. & Tabony, J. Ground-based methods reproduce space-flight experiments and show that weak vibrations trigger microtubule self-organisation. Biophys. Biochem. 121, 1–6 (2006).

    CAS  Google Scholar 

  150. 150

    Korb, T. et al. Integrity of actin fibers and microtubules influences metastatic tumor adhesion. Exp. Cell Res. 299, 236–247 (2004).

    CAS  PubMed  Article  Google Scholar 

  151. 151

    Suresh, S. Biomechanics and biophysics of cancer cells. Acta Biomater. 3, 413–438 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  152. 152

    Kim, Y., Stolarska, M. A. & Othmer, H. G. The role of microenvironment in tumor growth and invasion. Prog. Biophys. Mol. Biol. 106, 353–379 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  153. 153

    Wang, N. & Ingber, D. E. Control of cytoskeletal mechanics by extracellular matrix, cell shape, and mechanical tension. Biophys. J. 66, 2181–2189 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154

    Ingber, D. E. From cellular mechanotransduction to biologically inspired engineering. Ann. Biomed. Eng. 38, 1148–1161 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  155. 155

    Wang, N. et al. Mechanical behavior in living cells consistent with the tensegrity model. Proc. Natl Acad. Sci. USA 98, 7765–7770 (2001). This paper details cellular structure and biomechanics as governed by the principles of tensegrity.

    CAS  PubMed  Article  Google Scholar 

  156. 156

    Maniotis, A. J., Chen, C. S. & Ingber, D. E. Demonstration of mechanical connections between integrins, cytoskeletal filaments and nucleoplasm that stabilize nuclear structure. Proc. Natl Acad. Sci. USA 94, 849–854 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157

    Ingber, D. E. Tensegrity I. Cell structure and hierarchical systems biology. J. Cell Sci. 116, 1157–1173 (2003).

    CAS  PubMed  Article  Google Scholar 

  158. 158

    Ingber, D. How cells (might) sense microgravity. FASEB J. 13, S3–S15 (1999). This paper reviews how cells may perceive, and respond mechanically, to alterations in gravity.

    CAS  PubMed  Article  Google Scholar 

  159. 159

    Stein, G. S. et al. Implications for interrelationships between nuclear architecture and control of gene expression under microgravity conditions. FASEB J. 13, S157–S166 (1999).

    CAS  PubMed  Article  Google Scholar 

  160. 160

    Guignandon, A. et al. Cell cycling determines integrin-mediated adhesion in osteoblastic ROS 17\\2.8 cells exposed to space-related conditions. FASEB J. 15, 2036–2038 (2001).

    CAS  PubMed  Article  Google Scholar 

  161. 161

    Xu, W. et al. Cell stiffness if a biomarker of the metastatic potential of ovarian cancer cells. PLoS ONE 7, e46609 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162

    Guck, J. et al. Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophy. J. 88, 3689–3698 (2005).

    CAS  Article  Google Scholar 

  163. 163

    Todd, P. Overview of the spaceflight radiation environment and its impact on cell biology experiments. J. Gravit. Space Phys. 11, 11–16 (2004).

    Google Scholar 

  164. 164

    Manti, L. Does reduced gravity alter cellular response to ionizing radiation? Radiat. Environ. Biophys. 45, 1–8 (2006).

    PubMed  Article  Google Scholar 

  165. 165

    Cucinotta, F. A. Once we know all the radiobiology we need to know, how can we use it to predict space radiation risks and achieve fame and fortune? Phys. Med. 17, 5–12 (2001).

    PubMed  Google Scholar 

  166. 166

    Dieriks, B. et al. Multiplexed profiling of secreted proteins for the detection of potential space biomarkers. Mol. Med. Rep. 4, 17–23 (2011).

    CAS  PubMed  Google Scholar 

  167. 167

    Durante, M. Biomarkers of space radiation risk. Radiat. Res. 164, 467–473 (2005).

    CAS  PubMed  Article  Google Scholar 

  168. 168

    Albi, E. et al. Thyroid cell growth: sphingomyelin metabolism as non-invasive marker for cell damage acquired during spaceflight. Astrobiol. 10, 811–820 (2010).

    CAS  Article  Google Scholar 

  169. 169

    Nichols, H. L. Zhang, N. & Wen. X. Proteomics and genomics of microgravity. Physiol. Genom. 26, 163–171 (2006).

    CAS  Article  Google Scholar 

  170. 170

    Grimm, D., Wise, P., Lebert, M., Richter, P. & Baatout, S. How and why does the proteome respond to gravity? Expert Rev. Proteom. 8, 13–27 (2011).

    Article  Google Scholar 

  171. 171

    Cao, Y., DePinho, R. A., Ernst, M. & Vousden, K. Cancer research: past, present and future. Nature Rev. Cancer 11, 749–754 (2011).

    CAS  Article  Google Scholar 

  172. 172

    Canadian Space Agency. Cancer treatment delivery. International Space Station Benefits for Humanity [online], (2012).

  173. 173

    Le Pivert, P. et al. Ultrasound guided combined cryoablation and microencapsulated 5-fluorouracil inhibits growth of human prostate tumors in xenogenic mouse model assessed by luminescence imaging. Technol. Cancer Res.Treat. 3, 135–142 (2004).

    CAS  PubMed  Article  Google Scholar 

  174. 174

    Le Pivert, P. et al. Percutaneous tumor ablation: microencapsulated echo-guided interstitial chemotherapy combined with cryosurgery increases necrosis in prostate cancer. Technol. Cancer Res. Treat. 8, 207–216 (2009).

    CAS  PubMed  Article  Google Scholar 

  175. 175

    Brown, C. S., Tibbits, T. W., Croxdale, J. G. & Wheeler, R. M. Potato tuber formation in the spaceflight environment. Life Support Biosph. Sci. 4, 71–76 (1997).

    CAS  PubMed  Google Scholar 

  176. 176

    Tibbitts, T. W., Croxdale, J. C., Brown, C. S., Wheeler, R. M. & Goins, G. D. Ground-based studies and space experiment with potato leaf explants. Life Support Biosph. Sci. 6, 97–106 (1999).

    CAS  PubMed  Google Scholar 

  177. 177

    Whelan, H. T. et al. Effect of NASA light-emitting diode irradiation on molecular changes for wound healing diabetic mice. J. Clin. Laser Med. Surg. 21, 67–74 (2003).

    PubMed  Article  Google Scholar 

  178. 178

    Hodgson, B. D. et al. Amelioration of oral mucositis pain by NASA near-infrared light-emitting diodes in bone marrow transplant patients. Support Care Cancer 20, 1405–1415 (2012).

    PubMed  Article  Google Scholar 

  179. 179

    Bjordal, J. M., Johnson, M. I., Iversen, V., Aimbire, F. & Lopes-Martins, R. A. Low-level laser therapy in acute pain: a systematic review of possible mechanisms of action and clinical effects in randomized placebo-controlled trials. Photomed. Laser Surg. 24, 158–168 (2006).

    CAS  PubMed  Article  Google Scholar 

  180. 180

    Albertini, R. et al. COX-2 mRNA expression decreases in the subplantar muscle of rat paw subjected to carrageenan-induced inflammation after low level laser therapy. Inflamm. Res. 56, 228–229 (2007).

    CAS  PubMed  Article  Google Scholar 

  181. 181

    Fucci, R. L. et al. Toward optimizing lighting as a countermeasure to sleep and circadian disruption in space flight. Acta Astronaut. 56, 1017–1024 (2005).

    PubMed  Article  Google Scholar 

  182. 182

    Brainard, G. C. et al. Sensitivity of the human circadian system to short-wavelength (420 nm) light. J. Biol. Rhythms 23, 379–386 (2008).

    PubMed  Article  Google Scholar 

  183. 183

    West, K. E. et al. Blue light from light-emitting diodes elicits a dose-dependent suppression of melatonin in humans. J. Appl. Physiol. 110, 619–626 (2011).

    PubMed  Article  Google Scholar 

  184. 184

    Blask, D. E., Dauchy, R. T., Brainard, G. C. & Hanifin, J. P. Circadian stage-dependent inhibition of human breast cancer metabolism and growth by the nocturnal melatonin signal: consequences of its disruption by light at night in rats and women. Integr. Cancer Therap. 8, 347–353 (2009).

    CAS  Article  Google Scholar 

  185. 185

    Glickman, G., Levin, R. & Brainard, G. C. Ocular input for human melatonin regulation: relevance to breast cancer. Neuro. Endocrinol. Lett. 23, 17–22 (2002).

    CAS  PubMed  Google Scholar 

  186. 186

    Blask, D. E. et al. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. 65, 11174–11184 (2005).

    CAS  PubMed  Article  Google Scholar 

  187. 187

    Schernhammer, E. S. et al. Rotating night shifts and risk of breast cancer in women participating in the nurses' health study. J. Natl Cancer Inst. 93, 1563–1568 (2001).

    CAS  PubMed  Article  Google Scholar 

  188. 188

    Schernhammer, E. S. et al. Night-shift work and risk of colorectal cancer in the nurses' health study. J. Natl Cancer Inst. 95, 825–828 (2003).

    PubMed  Article  Google Scholar 

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Acknowledgements

The authors dedicate this article in memory of Neil Alden Armstrong, with grateful appreciation and respect for his dedication and commitment to the exploration of space.

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Glossary

Nuclear force

The force holding together subatomic particles of the nucleus.

Electromagnetic force

The force associated with electric and magnetic fields.

Microgravity

Conditions of reduced gravity experienced specifically in the space environment.

Standard gravity

The natural force of attraction exerted by Earth on objects at or near its surface.

Low Earth orbit

A circular orbit extending to approximately 1,200 miles above the Earth's surface.

Gravity-dependent convection

Movement of fluid or gas affected by gravity.

Hydrodynamic shear

Stress arising in a fluid that is a function of the fluid velocity gradient and viscosity.

Sedimentation

The settling of solid material from a state of suspension.

Discoid

Disc-like shape of normal red blood cells.

Echinocytic

Abnormally shaped red blood cells exhibiting blunt spicule protrusions.

Spheroids

Three-dimensional multicellular clusters or aggregates.

Turbulence

Disordered motion in a fluid yielding disrupted and irregular flow.

Laminar flow

Fluid flow occurring in layers.

Clinostat

A horizontally rotating culture device.

Clinorotation

Rotation of a culture vessel about its horizontal axis.

Membrane oxygenation

Oxygen delivered to cells in a culture vessel via a gas-permeable membrane.

Gravitational vector

Unidirectional downward pull of the force of gravity.

Warm bore superconductive magnet

A strong field (100 T per m gradient) magnet, similar to a high-field nuclear magnetic resonance spectroscopic magnet.

Histogenesis

Growth and differentiation of cells to form specialized tissue.

Tensegrity

Also known as tensional integrity. A biomechanical principle of continuous tension or prestress that imparts stability and integrity in a spatial system and that facilitates responsiveness to environmental cues.

Prestress

Resting tension that provides structural integrity.

Oral mucositis

Inflammation and ulceration occurring in the mouth, often experienced as a side effect of receiving cancer chemotherapy.

Myeloablative treatment

The use of antitumour therapy to eliminate cancer in the bone marrow.

Light therapy

Administration of varying wavelengths of light to affect a biological outcome.

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Becker, J., Souza, G. Using space-based investigations to inform cancer research on Earth. Nat Rev Cancer 13, 315–327 (2013). https://doi.org/10.1038/nrc3507

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