In this week’s Nature, my eye was drawn to a Letter from Tan et al., (2011) discussing how inflammatory mechanisms influence tumorigenesis and metastatic progression, even in tumours that seemingly don’t involve pre-existing inflammation or infection such as breast and prostate cancers.
In advanced prostate cancer, metastasis is sadly inevitable. So far as we know, lymphocytes infiltrate the tumour, causing upregulation of nuclear factor-KappaB (RANK) ligand (RANKL) and lymphotoxin (see Luo et al., 2007).
RANK signalling controls osteoclastogenesis and bone resorption and targeting it with denosumab has been shown to reduce the incidence of skeletal related events (SRE) but not overall survival in prostate cancer (see Fizzazi et al., 2011):
and other advanced cancers, including multiple myeloma (see Henry et al., 2011). Overall survival was again not improved compared with zoledronic acid, as you can hear from this short podcast or read the accompanying editorial in the JCO from Dr Jack West of Swedish on the topic, which was both fair minded and well written, discussing additional factors that need to be considered, including costs, something that is all too often swept under the carpet.
What is less well known, however, is the source of RANKL and it’s role in metastasis. Tan and colleagues therefore decided to take a closer look at this.
What did they do?
In their research, Tan et al., (2011) decided to evaluate whether RANKL, RANK and IKK-a (nuclear factor kinase-alpha) are involved in cancer metastasis. IKK-a is a protein kinase needed for the self renewal of cancer progenitors. The question is, how do all these relate? They used various cell lines and models to explore the relationships.
The NF-kB pathway looks like this:
What did they find?
The results showed that RANK signalling in cancer cell lines overexpressing Erbb2 (HER2) was important for pulmonary metastasis. This is also potentially relevant to breast cancer, since HER2 is frequently overexpressed in metastatic disease.
Using MT2 cells in Ragl-/- mamary glands, they looked at whether RANKL was involved in metastatic spread. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcriptional factor produced by T cells and were located next to stromal cells.
In all, the authors concluded that:
“Targeting RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.”
The challenge here though, is that while the preclinical models are very appealing in theory, in the clinic we must not forget that a significant reduction in SRE does not necessarily mean that patients live longer, as witnessed by the lack of OS benefit in the trials mentioned above.
Tan, W., Zhang, W., Strasner, A., Grivennikov, S., Cheng, J., Hoffman, R., & Karin, M. (2011). Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling Nature, 470 (7335), 548-553 DOI: 10.1038/nature09707
Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, & Karin M (2007). Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature, 446 (7136), 690-4 PMID: 17377533
West, H. (2011). Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases From Solid Tumors: Incremental Benefit, Debatable Value Journal of Clinical Oncology DOI: 10.1200/JCO.2010.33.5596
Henry, D., Costa, L., Goldwasser, F., Hirsh, V., Hungria, V., Prausova, J., Scagliotti, G., Sleeboom, H., Spencer, A., Vadhan-Raj, S., von Moos, R., Willenbacher, W., Woll, P., Wang, J., Jiang, Q., Jun, S., Dansey, R., & Yeh, H. (2011). Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma Journal of Clinical Oncology DOI: 10.1200/JCO.2010.31.3304
Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, & Goessl C (2011). Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet PMID: 21353695