Can Cancer Treatment Be Causing Metastatic Spread?
Targeted therapies could be changing the tumor microenvironment, causing treatment-induced metastasis.
Anticancer treatments, with their proven tumor-reducing benefits, could in fact also be paving the way for metastatic spread. Decades of preclinical studies demonstrate this paradox, however these data have largely been ignored—at least in part because most of the data have been derived from animal models.1
The problem of therapies simultaneously inhibiting tumor growth and promoting metastasis may be partly due to the use of mouse tumor models to study treatment effects at different stages of disease, wrote John Ebos, PhD, of Roswell Park Cancer Institute, Buffalo, NY.
“A significant challenge in treating metastasis in animal models tends to be variability,” wrote Dr. Ebos, “which may stem in part from nonstandard protocols for endpoints and techniques for disease quantification.” It's more difficult to assess the complex process of metastasis than it is to quantify localized effect of therapies, and it's also difficult to obtain reproducible results in mouse models.
Further confounding the problem is the fact that tumor growth responds differently to therapies depending on location and stage. We still don't know exactly how tumor-induced metastasis (TIM) originates, and it may be an even bigger problem than we realize.
“Prometastatic responses to treatment may play a significant role in treatment resistance,” wrote Dr. Ebos. “Of significance is whether such negative effects originate primarily from the tumor or the host.”
Targeted Therapy and the Tumor Microenvironment
It is possible that targeted therapies are preparing conditions in both the tumor and the microenvironment to support metastasis. Emerging and existing therapies can induce myriad host and tumor cell secretory programs that work together to regulate a flurry of proinflammatory cytokines, chemokines, and extracellular-matrix remodeling factors.
Targeted therapies may have the potential for blocking the tumor microenvironment (TME), thus impacting metastasis. Angiogenesis inhibitors, such as the vascular endothelial growth factor receptor (VEGF) inhibitors have been one of the more promising group of targeted therapies, but their long-term effect remains uncertain.
Their increasing use could have unexpected results. Ten VEGF pathway inhibitors have been approved since 2004.There has been a lack of enduring responses from patients, and a number of antiangiogenic drug resistance mechanisms have been described.
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Additionally, there is growing evidence that targeting nontumor stromal components may activate a bevy of compensatory mechanisms in the TME that can limit therapeutic efficacy and even increase metastatic disease. And in preclinical studies, VEGF has been shown to inhibit tumor progression – but also induce a more aggressive phenotype.
But there's still hope for targeted therapies. Dr. Ebos noted that “preclinical results stand in stark contrast with the benefits of antiangiogenic treatment, often observed in the same models, simply with modified experimental models.”
It is possible that TIM following TME therapy may only occur once therapy has stopped, which may mean that patients receiving certain antiangiogenic therapies could benefit from frequent breaks in dosing periods.
Closing the Gap
Translating the phenomenon of TIM in preclinical studies to human disease is still a difficult prospect: clinical evidence remains limited, and there is a gap between clinical trials that involve patients with highly metastatic, treatment-refractory disease and mouse models.
Dr. Ebos said it is time to close that gap by expanding the discussion around TIM to include a more detailed investigation of the clinical translation of animal studies.
"If it is found that TIM-related mechanisms are masking overall benefits of therapy, greater consideration must be given to how the TIM phenomena can be mitigated," he wrote. "And it must be determined whether treatment-induced changes in tumor biology are the result of mechanisms related to TIM observed in preclinical studies."
- Ebos J. Prodding the Beast: Assessing the impact of treatment-induced metastasis. Cancer Research 2015; 75(15):3427-3435.