It now appears that tetracyclines like doxycycline work by triggering increased production of lipid phosphate phosphatases on cell surfaces, which break down lysophosphatidate and decrease inflammamtion.5

Dr Brindley and his colleagues hope to develop strategies for targeting microenvironments and tumors with LPA signaling antagonists. Three autotaxin/LPA-targeting agents are undergoing phase 2 clinical study for idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.1

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“Our experience with mouse models of breast cancer demonstrates that inhibiting autotaxin alone has a transient effect in decreasing tumor growth,” he explained. “Very few monotherapies for cancer show long-term efficacy in the majority of patients. Our work demonstrates that inhibiting autotaxin and LPA signaling improves the efficacy of several chemotherapies.”

Dr Brindley’s team is also exploring the hypothesis that disrupting LPA in tumor microenvironments will improve the efficacy of radiotherapy and decrease radiation-induced fibrosis.

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“We showed that a single dose of radiation to human breast adipose tissue increases the production of autotaxin and expression of LPA1 and LPA2 receptors — and it produces a general inflammatory response,” he said.

The researchers are also exploring ways of targeting the LPA pathway in tumor tissue.

“The product of the PLPP1 gene is lipid phosphate phosphatase-1, which degrades extracellular LPA,” Dr Brindley said. “Consequently, decreased expression of LPP1 allows for increased signaling by LPA. We showed [in mice] that increasing the expression of LPP1 in breast cancer cells decreases the growth of breast tumors and metastases by about 80%.”2

While the team’s efforts focus on the role of breast adipose tissue in stimulating LPA signaling, Dr Brindley believes LPA will prove relevant for other cancers as well. Upregulation of LPA receptors is linked, for example, to more invasive tumor phenotypes in several cancers.

“Autotaxin derived from abdomen adipose tissue could also be a component in the poor prognosis in colonic, ovarian, and pancreatic cancers,” Dr Brindley said.

References

  1. Benesch MGK, Yang Z, Tang X, Meng G, Brindley DN. Lysophosphatidate signaling: the tumor microenvironment’s new nemesis. Trends Cancer. 2017 Oct 2. doi: 10.1016/j.trecan.2017.09.004 [Epub ahead of print]
  2. Tang X, Benesch MG, Dewald J, et al. Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice. J Lipid Res. 2014;55(11):2389-400. doi: 10.1194/jlr.M053462
  3. Meng G, Tang X, Yang Z, et al. Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy. FASEB J. 2017;31:4064-77. doi: 10.1096/fj.201700159R
  4. Leblanc R, Lee SC, David M, et al. Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone. Blood. 2014;124:3141-50.
  5. Tang X, Wang XY, Zhao YY, Curtis JM, Brindley DN. Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-kappa B activation. Mol Cancer. 2017;16:36. doi: 10.1186/s12943-017-0607-x

Topics:

Breast Cancer