Although cancer initially starts in one location, when it metastasizes it is notoriously difficult to treat.  In its metastasized state, the disease also accounts for most cancer deaths.

Treating metastatic cancer, especially if cancer has spread to different locations in the body, is a major challenge. Patients with metastatic tumors are often unresponsive to existing therapies, and long-term remission in treating these patients is far less likely than it is for patients diagnosed with localized cancer. Until recently, the underlying reason was unclear.

Heide L. Ford, Ph.D., Associate Director of basic research at the University of Colorado Cancer Center Credit University of Colorado Cancer Center. Photo courtesy: © 2021 University of Colorado Cancer Center; Used with permission.

Better understanding
However, based to new research published in Oncogene from the lab of University of Colorado Cancer Center associate director of basic research Heide Ford, Ph.D., in collaboration with Michael Lewis, Ph.D., from Baylor College of Medicine, doctors may soon have a better understanding of one mechanism by which metastasis happens, and of potential ways to slow it down.[1]

“Metastasis is a huge problem nobody’s tackled very well,” noted Ford, who holds the Grohne Endowed Chair in Cancer Research at the University of Colorado School of Medicine.

“People don’t know how to inhibit the process of metastasis, nor how to inhibit the growth of metastatic cells at secondary sites. And that’s what kills most cancer patients. A lot of common drugs, whether they’re targeted drugs or chemotherapies that are less targeted, do pretty well at inhibiting the primary tumor, but by the time cells metastasize, they’ve changed enough that they don’t get inhibited by those drugs,” Ford said.

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Epithelial-to-mesenchymal transition
The transformation Ford and her team are studying happen when cells called epithelial cells, which are more adherent to one another and less likely to spread to other parts of the body, start to take on the characteristics of mesenchymal cells, which are more migratory and more likely to invade other parts of the body. This transformation is referred to as the epithelial-to-mesenchymal transition or EMT.

EMT plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis.[2]

These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance, and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse.[2]

“When the epithelial cancer cells take on these characteristics of mesenchymal cells, they become less attached to their neighbor and they become more able to degrade membranes, so they can get into the bloodstream more easily,” Ford says.

In 2017, Ford published a paper in which she presented findings demonstrating that the metastasis process is helped along when cells that have undergone the epithelial-to-mesenchymal transition start “talking” to cells that haven’t, making those cells more likely to gain metastatic properties.[3]

In a new paper published in December, Ford and her team, in a collaborative study done with Lewis and colleagues at Baylor College of Medicine, posit that the crosstalk is facilitated by a naturally occurring protein called vascular endothelial growth factor C (VEGF-C), is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family.[1]

“VEGF-C is secreted by the cells. It binds to receptors on these neighboring cells and then activates a pathway called the hedgehog signaling pathway, though it bypasses the traditional way of activating this pathway,” Ford explained.

“[This process] turns on a signaling mechanism that ultimately results in activation of a protein called GLI that makes these cells more invasive and more migratory,” she added.

In the new paper, Ford, Lewis, and their team researchers show that inhibiting the production of VEGF-C may significantly slow metastasis.

“If you take out the receptor that receives the signal from the cells that have not undergone a transition, or if you take VEGF-C out of the mix, you can’t stimulate metastasis to the same degree,” Ford noted.

“If you remove that ability for these different cell types to crosstalk, now these cells that never underwent a transition can’t move as well anymore. They can’t metastasize as efficiently.”

The researchers are now in the early stages of animal trials to find out the best way to target that signaling pathway in order to better inhibit metastasis. They want to find out if they can stop metastasis from happening at all, and if they can slow its progression in patients in whom the metastatic process has already begun — and to see if they can inhibit tumor growth at the secondary site.

“For many years, people said there was no point in finding inhibitors to metastasis because, by the time someone comes into the clinic, the horse is out of the barn, so to speak. The cells have already gotten out of the primary tumor and you can’t do anything about it,” Ford explained.

“But that’s not necessarily true. Now, data show that if you have cells that have metastasized to a second site — say you have breast cancer and the cells went into the lungs — those cells that are in the lungs could in fact start metastasizing to other sites. You want to stop that process no matter where you are in this progression,” she concluded.

Author disclosures
Conflict of Interest Michael Lewis, Ph.D., from Baylor College of Medicine, a co-author of the study, is a founder and Limited Partner in StemMed Ltd, and a founder and manager in StemMed Holdings, its general partner. He is also a founder and equity stakeholder in Tvardi Therapeutics Inc.

[1] Kong D, Zhou H, Neelakantan D, Hughes CJ, Hsu JY, Srinivasan RR, Lewis MT, Ford HL. VEGF-C mediates tumor growth and metastasis through promoting EMT-epithelial breast cancer cell crosstalk. Oncogene. 2021 Feb;40(5):964-979. doi: 10.1038/s41388-020-01539-x. Epub 2020 Dec 9. PMID: 33299122; PMCID: PMC7867573.
[2] Zhang Y, Weinberg RA. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018 Aug;12(4):361-373. doi: 10.1007/s11684-018-0656-6. Epub 2018 Jul 24. PMID: 30043221; PMCID: PMC6186394.
[3] Neelakantan D, Zhou H, Oliphant MUJ, Zhang X, Simon LM, Henke DM, Shaw CA, Wu MF, Hilsenbeck SG, White LD, Lewis MT, Ford HL. EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells. Nat Commun. 2017 Jun 12;8:15773. doi: 10.1038/ncomms15773. Erratum in: Nat Commun. 2018 Nov 12;9(1):4720. PMID: 28604738; PMCID: PMC5472791.

Featured image: metastasis. Image courtesy: © 2020/2021 The Regents of the University of Colorado | Used with permission.

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