Breast Cancer Cells in Microgravity: New Aspects for Cancer Research

Abstract

Breast cancer is the leading cause of cancer death in females. The incidence has risen dramatically during recent decades. Dismissed as an "unsolved problem of the last century", breast cancer still represents a health burden with no effective solution identified so far. Microgravity (µg) research might be an unusual method to combat the disease, but cancer biologists decided to harness the power of µg as an exceptional method to increase efficacy and precision of future breast cancer therapies. Numerous studies have indicated that µg has a great impact on cancer cells; by influencing proliferation, survival, and migration, it shifts breast cancer cells toward a less aggressive phenotype. In addition, through the de novo generation of tumor spheroids, µg research provides a reliable in vitro 3D tumor model for preclinical cancer drug development and to study various processes of cancer progression. In summary, µg has become an important tool in understanding and influencing breast cancer biology.

Keywords: apoptosis; cancer therapeutic targets; cell adhesion; cytoskeleton; in vitro 3D tumor model; metastasis; proliferation.

Figure 1

(a) Under µg conditions, breast cancer cells grow into two distinct populations, characterized by hugely different morphologies. (b) Genes regulated in s-µg-induced multicellular spheroids (MCS) formation of MCF-7 cells [50,51,53]. First MCS were detectable after 24 h of random positioning. ▲, upregulation; ▼, downregulation; (c) STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) interaction network of proteins encoded by the regulated genes. Biological processes that are important both in cancer progression and in MCS formation are colorized. Blue, regulation of cell adhesion (Gene Ontology process GO:0030155); red, cell migration Gene Ontology process GO: 0016477). Gene symbols: ACTB, β-actin; ANXA1/2, annexin 1/2; BAX, Bcl-2-associated X protein; BCAR1, breast cancer anti-estrogen resistance protein 1; CASP8, caspase-8; CAV2, caveolin 2; CDH1, E-cadherin; CTGF, connective tissue growth factor; CXCL8, interleukin-8; CYC1, cytochrome c1; EZR, ezrin; FAS, Fas cell surface death receptor; FN1, fibronectin; ICAM1, intercellular adhesion molecule 1; IKBKG, inhibitor of NF-κB kinase regulatory subunit gamma; ITGB1, integrin-β1; KRT8, cytokeratin; MSN, moesin; NFKB1, nuclear factor kappa B subunit 1; NFKBIA, NF-κB inhibitor A; PARP1, poly [ADP-ribose] polymerase 1; RDX, radixin; TP53, tumor protein p53; TUBB, β-tubulin; VEGFA, vascular endothelial growth factor A. Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0).

Figure 2

(a) Time course images of MCF-7 cells taken on board of the TEXUS-54 sounding rocket during microgravity in comparison to a control image taken 5 min prior to launch. The arrows indicate changes in F-actin (green channel) or α-tubulin (red channel). F-actin cytoskeleton shows appearance of filopodia- and lamellipodia-like structures, accumulation of F-actin, while α-tubulin shows a loose structure and rearrangement of the cytoskeleton. (b) Subsequent cellular alterations of adherently growing breast cancer cells after exposure to r-µg (modified from [54]). F-actin is shown as green lines, the extracellular matrix (ECM) in yellow. The effects observed on parabolic and sounding rocket flights were observed in a time-range from a few seconds until minutes. (c) Downstream key processes in both cell populations of human breast cancer cells during long-term exposure to s-µg. FP, filopodia; LP, lamellipodia; SF, stress fibers.

Figure 3

(a) Glandular MCF-7 spheroids grown in s-µg for 10 days. (b) Schematic diagram and special features of a glandular breast cancer spheroid.