Angiogenesis-targeting chemotherapy can triple metastasis, according to the Cancer Cell Journal.

A study reveals that tumor cells can stop the progression of cancer.

Cancer Cell Journal, January 17, 2012, available at

According to a recent study, a collection of understudied cells in the tumor microenvironment likely act as crucial barriers to the spread and advancement of cancer. These findings, which were published in the January 17 edition of Cancer Cell, imply that anti-angiogenic medicines, which reduce cancer by cutting off the blood supply to tumors, may unintentionally increase tumor aggressivity and propensity to spread.

Angiogenesis, or the growth of blood vessels, is a target in one method of cancer treatment. In this new study, senior author Raghu Kalluri, MD, PhD, Chief of the Division of Matrix Biology at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School (HMS), sought to determine whether focusing on a particular cell type, the pericyte, could inhibit tumor growth in a manner similar to that of other antiangiogenic medications. The tissue vasculature includes pericytes, which protect blood vessels and encourage their expansion. To start, Kalluri and his colleagues developed genetically modified mice to support the drug-induced pericyte depletion in developing tumors. The number of pericytes was then reduced by 60% via deletion in implanted mouse breast cancer tumors. Over a period of 25 days, they observed a 30% reduction in tumor volumes compared with wild-type controls. Contrary to conventional clinical wisdom, the researchers discovered that the modified mice exhibited a threefold increase in secondary lung tumors compared to the control mice, indicating that the cancers had spread. “The results were good if you just looked at tumor growth,” claims Kalluri. “However, when the complete picture was considered, blocking tumor vessels did not stop the spread of malignancy. In actuality, the cancer was growing. Kalluri and his team looked at the tumor’s microenvironment to determine what alterations were occurring at the molecular level in order to understand the mechanism underlying this enhanced metastasis. In tumors devoid of pericytes, they discovered a fivefold percentage increase in hypoxic regions. This suggested that the vascular within the tumor was weakening and becoming more leaky—even more so than it already is within most tumors—and that this was limiting the flow of oxygen to the tumor, says Kalluri. He continues, “Cancer cells initiate genetic survival strategies in response to hypoxia.” In order to accomplish this, the researchers discovered proof of epithelial-to-mesenchymal transition (EMT), a change that makes the cells more mobile so they can pass through those leaky vessels to new locations and changes their behavior to behave more like stem cells so they are better able to survive. The cells had undergone the transition, as evidenced by experiments that showed fivefold increases in the protein markers of EMT. Additionally, the team discovered a fivefold rise in Met activation, a receptor protein that facilitates cell migration and expansion.

Importantly, the scientists discovered that these molecular alterations took place inside the smaller, pericyte-depleted tumors that in the animal models had higher frequencies of secondary cancers in the lungs. According to Kalluri, “this demonstrated that smaller tumors are secreting more cancer cells into the circulation and promoting more metastasis.” We demonstrated that compared to a smaller tumor of the same kind with less pericyte coverage, a large tumor with strong pericyte coverage is less metastatic. The researchers’ next step was to conduct the same experiments in mice with primary tumors, but this time using cancer therapies Imatinib and Sunitinib rather than genetic programs to reduce pericyte numbers. Cancer therapies like Imatinib, Sunitinib, and others have been shown to decrease pericytes in tumors. And despite the fact that both imatinib and sunitinib reduced pericytes by 70%, the end outcome was the same: metastasis multiplied thrice. According to Kalluri, who repeated these same studies with implanted renal cell carcinoma and melanoma tumors, “We found that a big tumor with strong pericyte covering is less metastatic than a smaller tumor of the same type with less pericyte coverage.” Additional research revealed that the combination of the Met-inhibiting medicine and pericyte-depleting therapies effectively reduced EMT and metastasis. The researchers next looked at 130 breast cancer tumor samples with various cancer stages and tumor sizes and compared pericyte levels with prognosis to see if the results were applicable to patients. They discovered a correlation between samples with low pericyte counts in tumor vasculature and high levels of Met expression with the most aggressive tumors, distant metastasis, and 5- and 10-year survival rates under 20%. The head of the University of Texas MD Anderson Cancer Center, Ronald A. DePinho, adds that these discoveries are “very provocative” and will have an impact on clinical initiatives aimed at reducing tumor angiogenesis. These outstanding findings will help to inform and improve prospective cancer therapy strategies. For Kalluri, the research implies that several presumptions regarding cancer need to be reconsidered. According to Kalluri, “We must go back and audit the tumor to determine which cells promote development and aggression vs which cells play a protective role.” “Not everything is either/or. There are some cells within a tumor that, in some circumstances, are beneficial. Beth Israel Deaconess Medical Center offers

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