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Blocking single gene makes cancer cells nicer, study finds

May 3, 2013
Courtesy of Johns Hopkins University
and World Science staff

Some­what like the way that gently lift­ing a cat by the scruff of the neck seems to mag­ic­ally calm it down, block­ing a sin­gle gene in tu­mor cells makes them less vi­cious, a study has found.

That gene is nor­mally sup­posed to be turned off long be­fore we’re born—but in many can­cer cells it’s ab­er­rantly switched back on, giv­ing them embryo-like pow­ers of growth, sci­en­tists ex­plained. 

Before-and-after pictures (left and right, respectively), of two strains of cancer cells, called MDA-MB-231 (top panels) and Hs578T cells (bottom panels), after a treatment that disabled the gene HMGA1. (Courtesy PLoS One)


How­ev­er, they found that re­press­ing it in can­cer cells largely shuts down cell growth and a range of pro­cesses tu­mors need to en­large and spread to dis­tant sites. 

The re­search­ers hope tar­get­ing this “mas­ter reg­u­la­tor” gene may be a key to fu­ture treat­ments.

It’s “nor­mally turned off in adult cells, but it is very ac­tive dur­ing em­bry­on­ic de­vel­op­ment and in all highly ag­gres­sive tu­mors stud­ied to date,” said Lin­da Re­sar of Johns Hop­kins Uni­vers­ity in Bal­ti­more, Md., a re­search­er in­volved the work. 

“Switch­ing this gene off in ag­gres­sive can­cer cells dra­mat­ic­ally changes their ap­pear­ance and be­hav­ior.”

The find­ings were re­ported May 2 in the re­search jour­nal PLoS One.

Re­sar has long been in­ves­ti­gat­ing a group of re­lat­ed genes, called high mo­bil­ity group or HMG genes. Be­side their role in can­cer, they’re es­sen­tial for giv­ing stem, or im­ma­ture, cells their spe­cial pow­ers of growth and change—which is no co­in­ci­dence, she said. “Many in­ves­ti­ga­tors con­sid­er can­cer cells to be the evil twin of stem cells, be­cause like stem cells, can­cer cells must ac­quire spe­cial prop­er­ties to en­a­ble the tu­mor to grow and me­tas­ta­size or spread to dif­fer­ent sites,” she ex­plains.

Re­sar and her team have de­vised ways to block one of these genes, called HMGA1, in stem cells to study what it does. In pri­or work, they found the gene is needed for “re­pro­gram­ming” adult cells, like blood or skin cells, in­to stem cells that share most, if not all, prop­er­ties of em­bry­on­ic stem cells.

In the new work, the team ap­plied the same meth­ods to sev­er­al strains of breast can­cer cells, in­clud­ing so-called tri­ple neg­a­tive cells, which tend to be ag­gres­sive and re­sist even pow­er­ful ther­a­pies. The re­search­ers blocked HMGA1 “ex­pres­sion”—that is, the ac­ti­vity of the gene, mean­ing the pro­cess in which the body uses a gene’s DNA code to make a spe­cif­ic type of pro­tein, which usu­ally car­ries out some func­tion in the body.

Next, the re­search­ers watched the cells’ ap­pear­ance and growth pat­terns. 

“The ag­gres­sive breast can­cer cells grow rap­idly and nor­mally ap­pear spindle-shaped or thin and elon­gat­ed. Re­mark­ably, with­in a few days of block­ing HM­GA1 ex­pres­sion, they ap­peared round­er and much more like nor­mal breast cells grow­ing in cul­ture,” said Re­sar. The team al­so found that the cells with the sup­pressed gene grow very slowly and fail to mi­grate or in­vade new ter­ri­to­ry like their nas­ti­er cousins.

The team next im­planted tu­mor cells in­to mice. The tu­mors with HM­GA1 grew and spread to oth­er ar­eas, such as the lungs, they said, while those with the blocked gene did­n’t grow well in the breast tis­sue or spread to dis­tant sites.

“From pre­vi­ous work, we know that HMGA1 turns on many dif­fer­ent genes needed dur­ing very early de­vel­op­ment, but it’s nor­mally turned off by the time we’re born,” said post­doc­tor­al fel­low Sandeep Shah, who led the stu­dy. “Flip­ping that mas­ter reg­u­la­tor back on seems to be nec­es­sary for a can­cer to be­come highly ag­gres­sive, and now we’ve seen that flip­ping HMGA1 off again can re­verse that ag­gres­sive be­hav­ior.”

The next step, Re­sar said, is to try to de­vel­op a ther­a­py based on that prin­ci­ple. The team is work­ing with oth­er re­search­ers at Johns Hop­kins to see wheth­er HMGA1-block­ing mo­le­cules could be de­liv­ered to tu­mors in­side sub-microscopic par­t­i­cles, or nanopar­t­i­cles. Anoth­er pos­si­ble ap­proach, she said, would be to block not HMGA1 it­self, but one of the path­ways or pro­cesses that it af­fects.


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Somewhat like the way that gently lifting a cat by the scruff of the neck seems to magically calm it down, blocking a single gene in tumor cells makes them less vicious, a study has found. That gene is normally supposed to be turned off long before we’re born—but in many cancer cells it’s aberrantly switched back on, giving them embryo-like powers of growth, scientists explained. However, they found that repressing it in cancer cells largely shuts down cell growth and a range of processes tumors need to enlarge and spread to distant sites. The researchers hope targeting this “master regulator” gene may be a key to future treatments. It’s “normally turned off in adult cells, but it is very active during embryonic development and in all highly aggressive tumors studied to date,” said Linda Resar of Johns Hopkins University in Baltimore, Md., a researcher involved the work. “Switching this gene off in aggressive cancer cells dramatically changes their appearance and behavior.” The findings were reported May 2 in the research journal PLoS One. Resar has long been investigating a group of related genes, called high mobility group or HMG genes. Beside their role in cancer, they’re essential for giving stem, or immature, cells their special powers of growth and change—which is no coincidence, she said. “Many investigators consider cancer cells to be the evil twin of stem cells, because like stem cells, cancer cells must acquire special properties to enable the tumor to grow and metastasize or spread to different sites,” she explains. Resar and her team have devised ways to block one of these genes, called HMGA1, in stem cells to study what it does. In prior work, they found the gene is needed for “reprogramming” adult cells, like blood or skin cells, into stem cells that share most, if not all, properties of embryonic stem cells. In the new work, the team applied the same methods to several strains of breast cancer cells, including so-called triple negative cells, which tend to be aggressive and resist even powerful therapies. The researchers blocked HMGA1 “expression”—that is, the activity of the gene, meaning the process in which the body uses a gene’s DNA code to make a specific type of protein, which usually carries out some function in the body. Next, the researchers watched the cells’ appearance and growth patterns. “The aggressive breast cancer cells grow rapidly and normally appear spindle-shaped or thin and elongated. Remarkably, within a few days of blocking HMGA1 expression, they appeared rounder and much more like normal breast cells growing in culture,” said Resar. The team also found that the cells with the suppressed gene grow very slowly and fail to migrate or invade new territory like their nastier cousins. The team next implanted tumor cells into mice to see how the cells would behave. The tumors with HMGA1 grew and spread to other areas, such as the lungs, they said, while those with the blocked gene didn’t grow well in the breast tissue or spread to distant sites. “From previous work, we know that HMGA1 turns on many different genes needed during very early development, but it’s normally turned off by the time we’re born,” said postdoctoral fellow Sandeep Shah, who led the study. “Flipping that master regulator back on seems to be necessary for a cancer to become highly aggressive, and now we’ve seen that flipping HMGA1 off again can reverse that aggressive behavior.” The next step, Resar said, is to try to develop a therapy based on that principle. The team is working with other researchers at Johns Hopkins to see whether HMGA1-blocking molecules could be delivered to tumors inside sub-microscopic particles, or nanoparticles. Another possible approach, she said, would be to block not HMGA1 itself, but one of the pathways or processes that it affects.