Tracing the Origins of Minimal Residual Disease

A recent review discussed how tumor cells generate resistance to cancer treatment, giving rise to the minimal residual disease (MRD) that leads to relapse or secondary tumors.

Although advancements in cancer have been many, disease relapse is still a hurdle for many types of tumors and malignancies, and there is an urgent need to overcome tumor resistance. Writing in Life, the authors aimed to describe the genetic, molecular, and evolutionary perspectives that come into play in MRD.

More needs to be understood about how MRD forms, they wrote. Cancer cells have evolved to evade cytotoxic therapies (ie, chemotherapy and radiotherapy) by slowing down their rate of cell division; then they reactivate once the cytotoxic therapy is stopped, thus preventing true remission. “In many cases, drug toxicity only partially affects MRD viability, since these effects are mitigated by lowering the intracellular concentration of the compound. This is achieved either by expelling the drug out of the cells or by decreasing its uptake,” the authors said.

The channel protein called P-glycoprotein is linked with increased resistance to drugs created in Chinese hamster ovary cells; other research has found that when DNA from resistant cells is transferred to nonresistant cells, the nonresistant cells become resistant as well, correlating with higher P-glycoprotein expression.

Other research has shown that MRD cells may harbor genetic mutations that block cell death, such as p53 or Bcl2.

In some tumor types, MRD may act as cancer stem cells, fueling their own growth.

In addition, tumor-initiating cells possess the ability to self-renew, are highly tumorgenic, and are key for progression, recurrence, and metastasis; these cells are very drug resistant.

From an evolutionary perspective, there are 2 schools of thought as to how resistant cells emerge. In one, the Lamarckian principle, it is believed that “an external stress source pushes organisms’ changes,” the authors said, and some cells may acquire an ability to survive.

The Darwinian point of view claims that these “innate changes are already present independently from the stress sources” and some cells may be naturally resistant regardless of the external changes.

The review also looked at in vitro and in vivo models of tumor resistance when evaluating the efficacy and toxicity of anticancer drugs.

In vitro models typically use stabilized cell lines or primary cell lines from human or murine tissue. The authors noted that during culturing, cells may harbor de novo mutations and chromosomal aberrations and may acquire genetic differences from the primary tumor.

3D cell culturing has recently been used in drug testing as it costs less, has reduced ethical concerns, and can help develop biobanks. In vitro models are indispensable for drug repurposing studies, the authors said.

In vivo modeling through preclinical animal models can pinpoint underlying tumor resistance and propose possible ways to bypass the resistance. The 4 main ones are cell-line-derived tumor xenograft models, patient-derived xenograft models, an immunocompetent mouse model, and genetically engineered mouse models.

In addition, high-throughput genomic techniques can choose patients who can benefit from new single-drug or combination treatments, the authors said.

Reference

Mitola G, Falvo P, Bertolini F. New insight to overcome tumor resistance: An overview from cellular to clinical therapies. Life (Basel). 2021;11(11): 1131. doi: 10.3390/life11111131