Research Aims to Explain Paclitaxel's Ability to Both Treat and Spread Cancer

New research has identified a gene that enables paclitaxel to spread cancer to the lungs even as it shrinks tumors in the breast.

Paclitaxel, a chemotherapy drug used to treat breast cancer, can also have the paradoxical and unwanted effect of enabling metastasis to the lungs and increasing the number of circulating tumor cells. A recent study published in Proceedings of the National Academy of Sciences finds that paclitaxel and cancer metastasis are linked by the Atf3 gene.

Researchers used mice models to analyze the mechanisms of metastases in response to paclitaxel at both, the primary tumor and the distant site where the cancer cells colonized. Consistent with previous research, paclitaxel reduced the size of the primary breast tumors, but exacerbated metastases in the lungs of the mice.

ATF3, a transcription factor, can be induced by several types of chemotherapy, including paclitaxel. Thus, the researchers tested its contribution to metastasis by comparing mice who harbored wild-type Atf3 and those in which the gene had been knocked out. The mice with wild-type Atf3 demonstrated a significantly higher metastatic burden after receiving paclitaxel than those without, who experienced almost no exacerbation of metastasis in response to paclitaxel.

Further analysis indicated that paclitaxel affected the tumor microenvironment of metastasis and blood vessel properties in tumors with ATF3 but not those without. These qualities can enable cancer cells to escape, which was supported by the finding of much higher circulating tumor cells in the mice with the Atf3 gene than in mice whose Atf3-knock out mice.

Paclitaxel was also shown to modify the lung microenvironment, making it easier for cancer cells to colonize, dependent on the presence of the Atf3 gene: the drug increased cancer cell seeding and increased the abundance of inflammatory monocytes in the lung if Atf3 was present. Atf3 also allowed paclitaxel to up-regulate the expression of chemokine (C-C motif) ligand 2, which influences cancer development.

To summarize these findings on the role of Atf3 in paclitaxel-induced metastasis, senior study author Tsonwin Hai, PhD, provided a metaphor. “This gene seems to do two things at once: essentially help distribute the ‘seeds’ (cancer cells) and fertilize the ‘soil’ (the lung),” Hai said in a press release from The Ohio State University.

Although these analyses were conducted in mice, the researchers pointed to genetic analyses, biomarker data, and survival rates in human patients that supported their theory that Atf3 changes the tumor environment at the metastatic sites to enable monocyte recruitment and suppress the immune system.

They suggested that further research should analyze the immunohistochemical makeup of patient samples in order to determine the impact of Atf3 on metastasis after paclitaxel and other cancer treatments.

“Because chemotherapy is an important treatment for cancer patients, dampening the effect of Atf3 may help improve the efficacy of chemotherapy,” the study concluded.