In recent years investigators have discovered that breast tumors are influenced by more than just the cancer cells within them. A variety of noncancerous cells, which in many cases constitute the majority of the tumor mass, form what is known as the “tumor microenvironment.” This sea of noncancerous cells and the products they deposit appear to play key roles in tumor pathogenesis.Among the key accomplices in the tumor microenvironment are mesenchymal stem cells (MSCs), a group of adult progenitor cells, which have been shown to help breast cancers maneuver and spread to other parts of the body.Now, new research sheds further light on how this spreading is happening. Led by investigators at Harvard-affiliated Beth Israel Deaconess Medical Center (BIDMC), the research demonstrates that the lysyl oxidase (LOX) gene is spurred to production in cancer cells as a result of their contact with MSCs, and once produced, can help ensure the spread of otherwise weakly metastatic cancer cells from primary tumors to the lung and bones. Described online in the Proceedings of the National Academy of Sciences (PNAS), this discovery not only provides key insights into the basic biology of tumor formation, but also offers a potential new direction in the pursuit of therapies for the treatment of bone metastasis.“We don’t have a lot of therapies that can target breast cancer once it has metastasized, particularly once cancer cells have lodged in the bone,” says senior author Antoine Karnoub, an investigator in the Department of Pathology at BIDMC and assistant professor of pathology at Harvard Medical School. “When breast cancer cells reach the skeleton, one way in which they cause damage is by breaking down bone tissue, which results in the bone’s rich matrix releasing numerous factors. These factors, in turn, feed the cancer cells, setting in motion a vicious cycle that leaves patients susceptible to fractures, pain, and further metastasis.”MSCs are nonhematopoietic progenitor cells predominantly produced in the bone marrow that generate bone, cartilage, fat, and fibrous connective tissue. They additionally support immune cell development and are recruited to inflammatory sites throughout the body to help shut down immune responses and regenerate damaged tissues, as might occur during wound healing. Several years ago, as a postdoctoral researcher at the Whitehead Institute of the Massachusetts Institute of Technology, Karnoub began exploring the idea that MSCs were migrating to tumors after mistaking the cancer sites for inflammatory lesions in need of healing.“We discovered that once MSCs had reached the tumor sites, they were actually helping in cancer metastasis, causing primary cancer cells to spread to other sites in the body,” he explains. In this new research, Karnoub wanted to find out — in greater molecular detail — how breast cancer cells respond to the influences of MSCs in order to better understand how cancer cells cross talk with recruited cells in the microenvironment.His scientific team first embarked on a straightforward experiment. “We took two dishes of cells, cancer cells and MSCs, and mixed them together,” Karnoub explains. After three days, the researchers removed the cancer cells and studied them to see how they had changed.“We found that the lysyl oxidase gene was highly upregulated in the cancer cells,” Karnoub says. “It turns out that when a cancer cell comes in contact with an MSC, it flips on this LOX gene, turning it up by a factor of about 100. So our next question was: What happens to the cancer cells when they encounter this boost of LOX that they themselves have produced?”The answer, as revealed in subsequent experiments, was that LOX was setting in motion a cell program called epithelial-to-mesenchymal transition (EMT). During EMT, cancer cells that usually clump together undergo a transformation into cells that exhibit decreased adhesion to their neighbors and go their own way. As a result, these cancerous cells are able to migrate, significantly enhancing their ability to metastasize.“When we put these cells back into mice, they not only formed tumors that metastasized to the lung, but also to the bone,” says Karnoub. “This makes you wonder whether the cancer cells in primary tumors have become so acclimated to interacting with bone-derived MSCs that they can now grow more easily in the bone once they leave the tumor.”The investigators also wanted to find out if, by going through the EMT process, cancer cells were also acquiring the phenotypes of another highly aggressive feature of malignant cancer cells, those of cancer stem cells within the cores of most tumors.“Cancer stem cells are believed to be responsible for the resurgence of tumors following chemotherapy treatment, and an increasing body of science is focused on understanding how CSCs function and how they originate,” says Karnoub. “The processes of EMT and CSC formation have been described as being closely coupled, and we asked whether LOX might be regulating CSC phenotypes, just as it was regulating EMT. To our surprise, this was not the case. This tells us that pathways that were once thought to be intimately intertwined and commonly tweaked may, in fact, be separate, and now we can start to tease out the respective circuitries with a bit more clarity.”Lastly, the investigators identified the mechanism that was enabling LOX to be turned on from outside the cell, a set of molecules called hyaluronic acid (HA) and CD44. “It turns out that the MSCs provide the HA while the cancer cells provide the CD44, and they work in tandem like a lock and key to upregulate LOX expression,” explains Karnoub, adding that antagonists to HA and CD44, already in extensive investigations and clinical exploration, might be of increased use from a clinical standpoint, perhaps in managing bone metastasis.To read the full story.
410 Severin St, Parramatta ParkWALK through the doors of this Parramatta Park house and be taken back to a glorious time when ABBA was “in”, Lillee and Thommo were petrifying Poms and the bright spark who invented Facebook was not yet born.The unique Severin St house has barely changed since the 1970s. “It is just a bit different, you certainly don’t see many homes like this around Cairns anymore,” said Hannah Fuller of Belle Property Cairns.“We have people walk through and say it reminds them of their grandparents’ house.”Set on almost 680sq m – a relatively large block for Parramatta Park – the three-bedroom red brick house has been described as a “renovator’s delight”.A rear patio is ideal for entertaining while the neat backyard has been well-maintained.Ms Fuller said Parramatta Park was becoming an increasingly sought-after suburb because of its proximity to town.“Many clients have bought into the area and are running successful Airbnb operations, it’s just so close to the city,” she said. More from newsCairns home ticks popular internet search terms3 days agoTen auction results from ‘active’ weekend in Cairns3 days agoDescribed as a “1970s gem”, the property at 410 Severin St is listed for offers in the low to mid $300,000s. The property is listed for offers in the low to mid $300,000s.According to CoreLogic, the average selling price for Parramatta Park houses was $472,500 as of May this year.The Tablelands man co-ordinating the sale, who asked to be known as Joe, said his parents had “absolutely loved” their many years living in the home.“We were actually keen for them to move years ago but they just loved it so much,” he said.“They were always playing billiards and listing to records – they were real party animals.“I remember once, about 25 years ago, a Japanese guy who was living around the corner offered them $450,000 for the place – but Dad said no.“It was when the Japanese were buying a lot in Cairns, and I guess Mum and Dad had no idea the downturn would happen – but they were very happy.”The property is open for inspection today from 10-10.30am
Once mocked, they are booming Garth A. RoseThere was a time when some South Floridians scoffed at shopping at dollar stores. However, as more families struggle with relatively low incomes they are turning to these low-price bargain stores. And, as the demand for bargains increase, dollar stores have sprung up across the region.They include national chains like Dollar Tree, Dollar General and Family Dollar. Dollar Tree currently has over 90 stores in South Florida. Florida is one of their largest markets, second only to California.Today’s discount retail has come far from its past of mangy products and dinky layouts. Many discount chains have overhauled their stores, including larger food selections, more health and cosmetic products and even pharmaceutical services.“The image of dollar stores has changed dramatically over the years,” says consumer analyst Paula Dalton of West Kendall. “Dollar stores are now reputable enterprises, and similar to the Woolworth chain of the past. There are over 30,000 dollar stores in the US today, a 25 percent growth rate since 2011. This exceeds the growth of Wal-Mart which has grown some 20 percent since 2011.”Dalton notes however that it’s the availability of dramatically-reduced prices that attracts new clients – often millennials setting up house, and shoppers who previously shunned dollar stores for traditional retailers.“The attractive prices dollar stores offer has a strong pull on customers,” says Dalton. “Plus, the quality of their merchandise has improved. These stores definitely meet the needs of customers with limited cash in their pockets.”Dalton predicts that competition from these discount stores could weaken sales from traditional retail and department stores.“To be profitable, most of the traditional stores catering to local consumers will need to cut prices to attract shoppers. This is what dollar stores do.”Miami resident, Tammy Saunds, said in the past she mocked her sisters for shopping regularly at dollar stores, but now confesses to be a regular customer.“These stores now have such a wide variety of goods of improved quality, that meets the needs of people who are hurting financially.” says Saunds.“I now purchase toiletries, snacks and kitchen-ware at dollar stores.”This recent boom seems like a renaissance for the typical American discount store, originally known as “dime stores”, which have a long history of serving consumers during harsh economic times since the 19th century.Dime stores grew in popularity after the American Civil War, selling a variety of inexpensive goods, meeting the demands of consumers who couldn’t afford the high inflationary prices of wartime.