Mesenchymal Stem Cells Induce Cell Proliferation, Inhibit Dexamethasone Effectiveness in MM

Mesenchymal stem cells (MSCs) are known to promote tumor growth and metastasis in multiple myeloma (MM), and a recent study published in Stem Cells International found that the presence of MSCs inhibits the antitumor effects of dexamethasone, a medication commonly used to treat MM.

MM is a hematological malignancy that weakens bone tissue, causes fractures, and negatively affects the immune system. For most patients, it is incurable, with a median survival rate of less than 65 months after diagnosis for any stage of disease. MSCs are one of the biggest cell populations in bone marrow stroma and have previously been linked to MM development in past studies.

“Interestingly, when MM occurs, MSCs exhibited different functional modes as normal MSCs,” study authors wrote, noting that MSC recruitment into tumor sites promotes growth and metastasis by regulating exosome secretion and cytokine release.

The corticosteroid dexamethasone is one of the most used medications in MM treatment, either alone or in tandem with other therapies. It works by relieving immune system inflammation and preventing MM lesions from recruiting more blood cells. Since dexamethasone typically prevents recruitment of more blood cells to tumor sites, the study authors aimed to find out how MSCs affect dexamethasone treatment success in MM.

Long intergenic noncoding (LINC) RNAs—noncoding transcripts of more than 200 nucleotides—have been linked to worsening disease and the pathogenesis of MM. This includes LINC00461, which was found to promote cell reproduction and was highly expressed in MM. A previous study found that LINC00461 is enriched in an exosome derived from MSC and LINC00461 knockdown can effectively suppress MM.

In the current study, the effects of MSC presence and the overexpression of LINC00461 in MM treated with dexamethasone were explored via human MM cell lines (OPM-2 and RPMI8226 cells) and human MSCs sourced from the American Type Culture Collection. OPM-2 or RPMI8226 cells were cocultured with MSCs either with or without dexamethasone and tested for cell viability 48 hours later.

Dexamethasone decreased the viability of OPM-2 and RPMI8226 cells, but the presence of MSCs increased cell viability compared with dexamethasone-treated cells. MSCs also decreased the percentage of apoptotic cells vs dexamethasone treatment, which increased the percentage of apoptotic cells. Dexamethasone also inhibited BCL-2 protein expression, which is involved in regulating apoptotic cell death, whereas MSCs increased BCL-2 expression. This suggests MSCs mitigated dexamethasone-induced cell apoptosis partially due to their BCL-2 regulation.

MSC presence was also shown to increase mRNA levels of LINC00461 in OPM-2 and RPMI8226 cells. The study authors constructed the LINC00461 overexpression cell lines and subsequently showed that knocking down LINC00461 reduced BCL-2 expression; dexamethasone further decreased BCL-2 expression when added to those cells. Overexpression of LINC00461, however, suppressed dexamethasone’s effectiveness, as well as decreased the percentage of apoptotic cells vs what was seen in dexamethasone-treated cells. Overall, LINC00461 knockdown consistently enhanced dexamethasone’s effects on cell viability and apoptosis rates.

“The presence of MSCs affected the effects of dexamethasone on cell proliferation, cell apoptosis, and cell cycle distribution. Interestingly, the overexpression of LINC00461 exhibited a similar mode as dexamethasone’s antitumor effects on MM cells,” the authors wrote.

These findings are in line with past research showing that MSCs increase cell proliferation in several cancer types, with the current study finding them to be inhibitive of the antitumor effects of dexamethasone in MM. LINC00461 has also been found to promote cell proliferation in other studies and in different cancer types.

“Taken together, MSCs inhibited the effects of dexamethasone on MM and its inhibitory effects were associated with LINC00461,” the authors concluded.

Reference

Deng M, Yuan H, Peng H, et al. Mesenchymal stem cells inhibit the effects of dexamethasone in multiple myeloma cells. Stem Cells Int. Published online April 4, 2022. doi:10.1155/2022/4855517