Caspase-8: The Possible Connection Between the Tumour and its Microenvironment

Holly -

Caspase-8 has been shown to be involved in apoptosis, and more recently studies have demonstrated its potential to regulate the composite of the tumour microenvironment. So, the question arises: can a tumour communicate with its microenvironment via the caspase-8 protein?

A caspase is an aspartate-specific cysteine protease. To break that down a little, aspartate and cysteine are both amino acids. Caspases are named in this way due to their highly specific cysteine protease activity - a cysteine residue found within the protease's active site induces nucleophilic attack and hence cleaves a target protein, at the C-terminal of an aspartic acid residue within the protein. In effect, this cleavage of the cysteine protease triggers apoptosis through various methods, all characteristic of apoptosis, including:

  • DNA fragmentation (splitting of DNA into smaller sections of DNA cutting at various points)
  • externalisation of phosphatidylserine on the membrane (moving the phosphatidylserine from the interior of the cell membrane (intracellular) to the exterior of the cell membrane (extracellular))
  • formation of apoptotic bodies (small membrane bound fragments that are removed by phagocytosis (engulfed by phagocytes (white blood cells)) without triggering an inflammatory response)

If a tumour causes downregulation of caspase-8, this can lead to tumour progression via the secretion of proteins into the tumour microenvironment that aid the development of the tumour according to a recent study by Kostova et al., 2020. If this is the case, then a drug which induces caspase-8 expression could be beneficial to patients. It has been shown previously that failure to regulate the expression of caspase-8 can lead to an imbalance between apoptosis and non-apoptosis, and this occurs both in the tumour, and the TME.

What is downregulation? Downregulation is ultimately a process whereby a cell decreases the quantity of a cellular component, for example a protein such as caspase-8, or RNA, in response to an external stimulus.

The tumour microenvironment contains a multitude of cytokines - proteins which are secreted by cells that can fall into various different categories including one key category in this case, interleukins. Interleukins are produced by a leukocyte and lead to an effect on another leukocyte. CCL2 and IL-6 are both examples of cytokines which can have their effects mimicked by other leukocytes known as macrophages, which have been polarised.

This polarisation can occur as a result of manipulation by caspase-8 inhibitors. The polarisation of macrophages using caspase-8 to give M1 and/or M2 macrophages has already been evidenced through a mouse model. The model exemplified that the polarisation was required in order for the differentiation of monocytes to occur. Furthermore, in relation to the previous article covering trabectedin and lurbinectedin (targeting the tumour microenvironment), both of these drugs have been shown to reduce the production of growth factors including the aforementioned CCL2 and IL-6. Moreover, this in term leads to changes in the cytokine expression found within the tumour microenvironment, as well as their typical function (which is inhibiting the growth of the primary tumour). Since it is know that caspase-8 can also interact with the growth factors, the suggestion that caspase-8 could play a significant role in communicating between the tumour and its microenvironment is further strengthened. In addition to this, caspase-8 also regulates angiogenesis, proposed by some to use an interleukin mediated pathway. As a result of this, drugs including trabectedin and lurbinectedin could therefore access the regulation of angiogenesis and cytokine expression through the regulation of caspase-8. Hence, their targeted therapeutic nature by which they can target the tumour's microenvironment could be explained.

The entire role of caspase-8 is currently unclear. The points below outline a few current thoughts:

  • Current research makes it apparent that caspase-8 could mediate whether the environment is pro-tumourigenic or anti-tumourigenic through the means of controlling how lymphocytes differentiate.
  • The investigation of potential signalling pathways between caspase-8, tumour cells (especially active ones) and the tumour microenvironment could aid a development in understanding how the tumour microenvironment becomes pro-tumourigenic.
  • Is caspase-8 relevant in mechanisms behind how an anti-tumour environment is maintained in non-tumour cells?
  • Do mutations interact with caspase-8 in any way? Or can mutations interact with the way that caspase-8 communicates between cells and their environments?

Thoughts to consider!

  • The TME contains numerous components which can regulate the development and progression of cancerous tumours
  • So far, developments in understanding the TME have led to the development of targeted therapeutics including trabectedin and lurbinectedin which target both the tumour cells, and the TME
  • The role of caspase-8 in both apoptosis and the regulation of TME composition demonstrates potential for caspase-8 to act as a link between the tumour itself and the TME
  • Advancements in the area surrounding caspase-8 could lead to the development of further targeted therapeutics which in turn could improve patient outlooks in many ways

Can you think of any more potential links that caspase-8 could have a role in? To help, I will give you four main broad categories to consider (all of which have been touched on at points in this article, but could be explored in more depth!):

  • Regulation
  • Therapeutic Targets
  • Controlling Cell Differentiation
  • Signalling

For example: a couple of additional points!

  • IL-6 causes monocytes to tend to differentiate into macrophages instead of dendritic cells. What are the potential effects of causing further differentiation to be favoured towards one type of cell? What advantages and disadvantages could that have?
  • Is it unique to this case? Could some of the other caspases which work in apoptosis or the immune response lead to any similar results? For reference (note how caspase-8 is the only one to appear in both an apoptotic and immune response category):
  • caspases -2, -8, -9 and -10 are apoptotic initiators
  • caspases -3, -6, and -7 are apoptotic effectors
  • caspases -1, -4, -5, -8 and -12 are related to immune response

I hope that this relatively short article has provided a few thinking points to open your mind to the sort of questions that can be asked in this area as a result of current studies and what we would like to know to advance next! Also, I hope that you are all looking forward to the upcoming articles now that I've finished a busy summer including jury service and much more! Lots of articles scheduled to be released this week! Looking forward to hearing from you all.

References

Antonopoulos, C. and Dubyak, G. (2014) Chemotherapy engages multiple pathways leading to IL-1β production by myeloid leukocytes OncoImmunology doi: 10.4161/onci.27499

Belgiovine, C., Bello, E., Liguori, M., Craparotta, I., Mannarino, L., Paracchini, L., Beltrame, L., Marchini, S., Galmarini, C. M., Mantovani, A., Frapolli, R., Allavena, P. and D’Incalci, M. (2017) Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models British Journal of Cancer doi: 10.1038/bjc.2017.205

Budd, R.C. (2002) Death receptors couple to both cell proliferation and apoptosisThe Journal of Clinical Investigation doi: 10.1172/JCI15077

Chomarat, P., Banchereau, J., Davoust, J. and Palucka, A.K. (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages Nature Immunology doi: 10.1038/82763

Cuda, C.M., Misharin, A.V., Khare, S., Saber, R., Tsai, F., Archer, A.M., Homan, P.J., Kenneth Haines III, G., Hutcheson, J., Dorfleutner, A., Budinger, G.R.S., Stehlik, C. and Perlman, H. (2015) Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner Arthritis Research & Therapy doi: 10.1186/s13075-015-0794-z

Ferraro-Peyret, C., Quemeneur, L., Flacher, M., Revillard, J-P. and Genestier, L. (2002) Caspase-independent phosphatidylserine exposure during apoptosis of primary T lymphocytes Journal of Immunology doi: 10.4049/jimmunol.169.9.4805

Germano, G., Frapolli, R., Simone, M., Tavecchio, M., Erba, E., Pesce, S., Pasqualini, F., Grosso, F., Sanflippo, R., Casali, P.G., Gronchi, A., Virdis, E., Tarantino, E., Pilotti, S., Greco, A., Nebuloni, M., Galmarini, C.M., Tercero, J.C., Mantovani, A., D’INcalci, M. and Allavena, P. (2010) Antitumor and Anti-inflammatory Effects of Trabectedin on Human Myxoid Liposarcoma Cells Cancer Research doi: 10.1158/0008-5472.CAN-09-2335

Kerr, J. F. R., Wyllie, A. H. and Currie, A. R. (1972) Apoptosis: A Basis Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics British Journal of Cancer doi: 10.1038/bjc.1972.33

Kostova, I., Mandal, R., Becker, S. and Strebhardt, K. (2020) The role of caspase-8 in the tumor microenvironment of ovarian cancer Cancer and Metastasis Reviews doi: 10.1007/s10555-020-09935-1

Larsen, A.K., Galmarini, C.M. and D’Incalci, M. (2016) Unique features of trabectedin mechanism of action Cancer Chemotherapy and Pharmacology doi: 10.1007/s00280-015-2918-1

Roca, H., Varsos, Z.S., Sud, S>, Craig, M.J., Ying, C. and Pienta, K.J. (2009) CCL2 and Interleukin-6 Promote Survival of Human CD11b+ Peripheral Blood Mononuclear Cells and Induce M2-type Macrophage Polarization Journal of Biological Chemistry doi: 10.1074/jbc.M109.042671

Salmena, L., Lemmers, B., Hakem, A., Matysiak-Zablocki, E., Murakami, K., Au, B.Y.B., Berry, D.M., Tamblyn, L., Shehabeldin, A., Migon, E., Wakeham, A., Bouchard, D., Yeh, W.C., McGlade, J.C., Ohashi, P.S. and Haken, R. (2003) Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity Genes & Development doi: 10.1101/gad.1063703

Tummers, B. and Green, D. R. (2017) Caspase-8; regulating life and death Immunological Reviews doi: 10.1111/imr.12541

Zhang, J-M. and An, J. (2007) Cytokines, Inflammation and Pain International Anaesthesiology Clinics doi: 10.1097/AIA.0b013e318034194e