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Docetaxel facilitates lymphatic-tumor crosstalk to promote lymphangiogenesis and cancer progression

Overview of attention for article published in BMC Cancer, July 2018
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Title
Docetaxel facilitates lymphatic-tumor crosstalk to promote lymphangiogenesis and cancer progression
Published in
BMC Cancer, July 2018
DOI 10.1186/s12885-018-4619-8
Pubmed ID
Authors

Alexandra R. Harris, Matthew J. Perez, Jennifer M. Munson

Abstract

Infiltration into lymphatic vessels is a critical step in breast cancer metastasis. Lymphatics undergo changes that facilitate metastasis as a result of activation of the cells lining lymphatic vessels, lymphatic endothelial cells (LECs). Inhibition of activation by targeting VEGFR3 can reduce invasion toward lymphatics. To best benefit patients, this approach should be coupled with standard of care that slows tumor growth, such as chemotherapy. Little is known about how chemotherapies, like docetaxel, may influence lymphatics and conversely, how lymphatics can alter responses to therapy. A novel 3D in vitro co-culture model of the human breast tumor microenvironment was employed to examine the contribution of LECs to tumor invasion and viability with docetaxel and anti-VEGFR3, using three cell lines, MDA-MB-231, HCC38, and HCC1806. In vivo, the 4T1 mouse model of breast carcinoma was used to examine the efficacy of combinatorial therapy with docetaxel and anti-VEGFR3 on lymph node metastasis and tumor growth. Lymphangiogenesis in these mice was analyzed by immunohistochemistry and flow cytometry. Luminex analysis was used to measure expression of lymphangiogenic cytokines. In vitro, tumor cell invasion significantly increased with docetaxel when LECs were present; this effect was attenuated by inhibition of VEGFR3. LECs reduced docetaxel-induced cell death independent of VEGFR3. In vivo, docetaxel significantly increased breast cancer metastasis to the lymph node. Docetaxel and anti-VEGFR3 combination therapy reduced lymph node and lung metastasis in 4T1 and synergized to reduce tumor growth. Docetaxel induced VEGFR3-dependent vessel enlargement, lymphangiogenesis, and expansion of the LEC population in the peritumoral microenvironment, but not tumor-free stroma. Docetaxel caused an upregulation in pro-lymphangiogenic factors including VEGFC and TNF-α in the tumor microenvironment in vivo. Here we present a counter-therapeutic effect of docetaxel chemotherapy that triggers cancer cells to elicit lymphangiogenesis. In turn, lymphatics reduce cancer response to docetaxel by altering the cytokine milieu in breast cancer. These changes lead to an increase in tumor cell invasion and survival under docetaxel treatment, ultimately reducing docetaxel efficacy. These docetaxel-induced effects can be mitigated by anti-VEGFR3 therapy, resulting in a synergism between these treatments that reduces tumor growth and metastasis.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 65 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 65 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 15 23%
Researcher 10 15%
Unspecified 6 9%
Student > Doctoral Student 5 8%
Student > Master 5 8%
Other 12 18%
Unknown 12 18%
Readers by discipline Count As %
Engineering 11 17%
Biochemistry, Genetics and Molecular Biology 10 15%
Medicine and Dentistry 7 11%
Unspecified 6 9%
Pharmacology, Toxicology and Pharmaceutical Science 4 6%
Other 11 17%
Unknown 16 25%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 February 2019.
All research outputs
#10,833,423
of 14,263,181 outputs
Outputs from BMC Cancer
#3,165
of 5,431 outputs
Outputs of similar age
#187,520
of 272,266 outputs
Outputs of similar age from BMC Cancer
#1
of 1 outputs
Altmetric has tracked 14,263,181 research outputs across all sources so far. This one is in the 20th percentile – i.e., 20% of other outputs scored the same or lower than it.
So far Altmetric has tracked 5,431 research outputs from this source. They receive a mean Attention Score of 4.1. This one is in the 34th percentile – i.e., 34% of its peers scored the same or lower than it.
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