One possible culprit being investigated is noncoding RNA MALAT1 (metastasis associated lung adenocarcinoma transcript-1), which is involved in epigenetic effects on gene expression, including genes implicated in metastasis. Noncoding RNAs like MALAT1 are increasingly recognized to play important roles in hematopoiesis, blood cell malignancies, and tumor metastasis.3,4

MALAT1 has been implicated in tumor growth and metastasis in solid tumors, including non-small cell lung cancer, osteosarcoma, renal cell carcinoma, oral squamous cell carcinoma, glioma, gastric cancer, and pancreatic cancer.3,5-8  

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More recently, researchers have started to explore its possible roles in myeloma progression — although Dr Fonseca was quick to note that extramedullary spread of myeloma is not the same thing as solid tumor metastasis.

“An important caveat it is that we do not think of myeloma or other hematological malignancies as having common pathways with metastasis as solid tumors have,” Dr Fonseca noted. “They are quite different in their biology and the concept of metastasis does not even apply for something like myeloma. Extramedullary disease really refers more to the ability of the cells to survive outside of the bone marrow micro environment. It is usually more a reflection of aggressiveness and one thing that needs to be further defined for this gene is how it is different from any other marker of disease progression.”

This summer, researchers in Japan reported that in patients undergoing chemotherapy for multiple myeloma, MALAT1 expression is significantly higher in extramedullary myeloma than myeloma cells confined to the bone marrow — and that expression was associated with poorer progression-free (PFS) and overall survival (OS).9 MALAT1 expression was not associated with p53 expression, they noted.9

“MALAT1 was significantly upregulated by bortezomib and doxorubicin,” reported lead study author Hiroshi Handa, MD, PhD, of Gunma University in Japan, and coauthors.9 Other chemotherapy agents did not induce elevated MALAT1 expression, though that was not detailed in their report, Dr Handa told Cancer Therapy Advisor.

Given what’s known about MALAT1, their research suggests that it acts as a stress-response gene that is upregulated by chemotherapy — meaning that chemotherapy can sometimes hasten disease spread, Dr Handa told Cancer Therapy Advisor. The findings also bolster the case that noncoding RNA plays important gene expression-modulating roles that can contribute to the progression and dissemination of cancers, he noted.

“This study is important and adds one more piece of information that suggests that genetic progression is what ultimately leads to extramedullary myeloma,” Dr Fonseca told Cancer Therapy Advisor.

That MALAT1 might increase the risk of extramedullary dissemination during chemotherapy is possible, Dr Landgren told Cancer Therapy Advisor — but the study findings are preliminary, he was quick to emphasize.

“More functional studies are needed to confirm and expand on these findings before we can consider this to be definitive,” Dr Landgren cautioned.

The proposed link between treatment and extramedullary disease is “possible, but it is only a theoretical possibility at this point,” agreed Dr Fonseca. “People have hypothesized that some of the chemotherapy agents that induce mutagenesis may favor progression of new clones towards more advanced stages, and perhaps by doing so, they could cause extramedullary disease. However, it is mostly a hypothetical framework, and patients should not refrain from using the treatment recommended by their physicians because of this considerations, at least at this point.”

Other recent reports have suggested that MENA and stress-induced Atf3 expression may modulate chemotherapy-induced metastasis in breast cancer.10,11

If the myeloma study’s findings are confirmed, MALAT1 RNA could be a promising target for the development of predictive biomarkers and new treatments.9,12 A research team in China separately reported that downregulating MALAT1 RNA expression with RNA interference slows proliferation and triggers apoptosis in vitro in multiple myeloma cell lines, and in animal models.12

References

  1. Hamed NAM. Extramedullary myeloma. Canc Therapy & Oncol Int J. 2016;1(3):1-2. doi: 10.19080/CTOIJ.2016.01.555561
  2. Sheth N, Yeung J, Chang H. p53 nuclear accumulation is associated with extramedullary progression of multiple myeloma. Leuk Res. 2009;33:1357-1360.
  3. Yoshimoto R, Mayeda A, Yoshida M, Nakagawa S. MALAT1 long non-coding RNA in cancer. Biochem Biophys Acta. 2016;1859:192-199.
  4. Wilkes MC, Repellin CE, Sakamoto KM. Beyond mRNA: the role of non-coding RNAs in normal and aberrant hematopoiesis. Molec Genet Metabol. 2017 July 21. doi: 10.1016/j.ymgme.2017.07.008 [Epub ahead of print].
  5. Zhou X, Liu S, Cai G, et al. Long non coding RNA MALAT1 promotes tumor growth and metastasis by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma. Sci Reports. 2015;5:15972. doi: 10.1038/srep15972
  6. Li Y, Wu Z, Yuan J, et al. Long non-coding RNA MALAT1 promotes gastric cancer tumorigenicity and metastasis by regulating vasculogenic mimicry and angiogenesis. Cancer Letters. 2017;395:31-44. doi: 10.1016/j.canlet.2017.02.035
  7. Gutschner T, Hammerle M, Eissmann M, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73(3):1180-1189.
  8. Grimaldi A, Zarone MR, Irace C, et al. Non-coding RNAs as a new dawn in tumor diagnosis. Semin Cell Devel Biol. 2017 July 21. [Epub ahead of print]. doi: 10.1016/j.semcbd.2017.07.035
  9. Handa H, Kuroda Y, Kimura K, et al. Long non-coding RNA MALAT1 is an inducible stress response gene associated with extramedullary spread and poor prognosis of multiple myeloma. Br J Haematol. 2017 August 2. doi: 10.1111/bjh.14882 [Epub ahead of print].
  10. Karagiannis GS, Pastoriza JM, Wang Y, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med. 2017;9:eaan0026. doi: 10.1126/scitranslmed.aan0026
  11. Chang YS, Jalgaonkar SP, Middleton JD, Hai T. Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis. Proc Natl Acad Sci USA. 2017;114(34):E7159-E7168.
  12. Liu H, Wang H, Wu B, et al. Down-regulation of long noncoding RNA MALAT1 by RNA interference inhibits proliferation and induces apoptosis in multiple myeloma. Clin Exp Pharmacol Physiol. 2017 June 30. [Epub ahead of print]. doi: 10.1111/1440-1681.12804

Topics:

Hematologic Cancers Multiple Myeloma