Tumors: What Does Not Kill Them Makes Them Stronger
What's Hot in Biology, November/December 2010
By Jeremy Cherfas
In the early 1970s the late Judah Folkman, then at Harvard Medical School, wrote a paper that broke entirely new ground in the treatment of cancer. Folkman observed that in culture many tumors stop growing at roughly the same size. Lack of blood supply was the reason, Folkman said. Without blood vessels to carry nutrients into the solid mass of tumor cells, the cells could not continue to divide and grow. Folkman saw this as a promising new approach to therapy: block the growth of blood vessels and starve the tumor to death.
Although the medical establishment was initially hostile, research continued and antiangiogenic drugs, which block the proliferation of blood vessels, were eventually shown to be of some benefit in some types of cancer. While this changed the clinical treatment of cancer, the outcome was often puzzling. Antiangiogenic drugs seemed to halt the growth of tumors, and patients stayed reasonably stable, but the drugs did not prolong the lives of patients by much. It was as if the drugs slowed the growth and spread of the tumor but were, in the end, overcome. The papers at #1 and #2 now give plentiful insights into what may be happening.
Published back to back in the same issue of Cancer Cell, the two papers show essentially similar results in essentially similar experiments. The two groups treated mice with antiangiogenic drugs and then observed what happened to tumors, either spontaneously developed in strains predisposed to cancer or from cultured cells injected intravenously. The drugs did indeed inhibit the primary growth of tumors, but seemed to shorten survival by also enhancing the ability of tumor cells to invade new tissues and spread.
"There are drugs that specifically target the process of metastasis; will they be more effective in combination with antiangiogenic drugs?"
The spread, or metastasis, of cancer from its tissue of origin to other tissues is more often the cause of death than the growth of the primary tumor, and while previous studies of antiangiogenic drugs confirmed that they slow the growth of the primary tumor, they did not look at metastasis. Robert Kerbel’s group in Toronto, Canada, at #2, asked what happened to injected tumors if the antiangiogenic treatment were stopped before the cancer cells were injected. Metastasis was faster and more widespread, leading to the suggestion that the drug had somehow primed or conditioned various organs to be more receptive to invasive cells.
The paper at #1, from a group led by Douglas Hanahan, at the University of California, San Francisco, and Oriol Casanovas at the Catalan Institute of Oncology in Spain, showed further that destroying the gene for an angiogenic receptor, a procedure functionally equivalent to blocking the receptor, had almost identical results, blocking primary tumor growth but enhancing metastasis.
What is going on? One suggestion is that the antiangiogenic treatment selects tumor cells that are better able to tolerate lack of oxygen. Tumor cells are in any case better able to withstand hypoxia. Cutting off the blood supply to the center of a tumor could well select for even more tolerant tumor cells. And those cells, if they did proliferate and spread would, by virtue of being resistant to hypoxia, also be more resistant to the antiangiogenic drugs.
Furthermore, tumor cells can respond to hypoxic environments by switching on processes that actually help them migrate out of the tumor and into surrounding organs, for example changing cell adhesion molecules on their surface. It thus seems likely that selection of hypoxia-resistant cells could account for the effects of antiangiogenic drugs. Hypoxic cells are also more resistant to radiotherapy and chemotherapy, which could partially explain the ultimately poor prognosis after antiangiogenic therapy.
On the other hand, hypoxic cells also have other ways of responding, and those too could increase the spread of cancers. Tumor cells can recruit circulating bone-marrow cells that then differentiate and supply more oxygen. They can take advantage of existing blood vessels, which are not blocked by the drugs, surrounding the vessel and spreading along it to invade other tissues. There is some suggestion from Hanahan and Casanovas that this is taking place in one of their experimental setups that uses a type of brain tumor, in which this kind of tumor spread is known to be more relevant.
And of course the big question is whether this new information about the effects of antiangiogenic drugs can be used to devise more effective treatments. There are drugs that specifically target the process of metastasis; will they be more effective in combination with antiangiogenic drugs? Maybe other forms of chemotherapy can be improved by altering the blood supply to tumors. There are even hints of individual differences in the angiogenic genes targeted by the blockers; perhaps the variants most susceptible to the ill-effects of antiangiogenesis could be screened out. Knowing the strengths of tumor cells could help to uncover further weaknesses.
Dr. Jeremy Cherfas is Science Writer at Bioversity International, Rome, Italy.
What's Hot in Biology |
|||
---|---|---|---|
Rank | Paper |
Cites This Period May-Jun 10 |
Rank Last Period Mar-Apr 10 |
1 | M. Paez-Ribes, et al., "Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis," Cancer Cell, 15(3): 220-31, 3 March 2009. [Catalan Inst. Oncology, L’Hospitalet de Llobregat, Spain; U. Calif., San Francisco; Osaka Med. Ctr. Cancer & Cardio. Dis., Japan; U. Barcelona, Spain] *416IC | 46 | + |
2 | J. M.L. Ebos, et al., "Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis," Cancer Cell, 15(3): 232-9, 3 March 2009. [Sunnybrook Health Sci. Ctr., Toronto, Canada; U. Toronto, Canada; Sunnybrook Odette Cancer Ctr., Toronto; Pfizer, La Jolla, CA] *416IC | 43 | + |
3 | J.C. Barrett, et al., "Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease," Nature Genetics, 40(8): 955-62, August 2008. [31 institutions worldwide] *331QF | 41 | 1 |
4 | A. Meissner, et al., "Genome-scale DNA methylation maps of pluripotent and differentiated cells," Nature, 454(7205): 766-70, 7 August 2008. [Whitehead Inst., Cambridge, MA; Broad Inst., Cambridge, MA; MIT, Cambridge; Harvard Med. Sch., Boston, MA] *334NH | 41 | + |
5 | T. Warne, et al., "Structure of a ß1-adrenergic G-protein-coupled receptor," Nature, 454(7203): 486-91, 24 July 2008. [MRC Lab. Molec. Bio., Cambridge, U.K.; U. Nottingham, U.K.] *329IC | 39 | + |
6 | M. Selbach, et al., "Widespread changes in protein synthesis induced by microRNAs," Nature, 455(7209): 58-63, 4 September 2008. [Max Delbruck Ctr. Molec. Med., Berlin, Germany; U. Glasgow, U.K.] *343XS | 6 | 10 |
7 | D. Baek, et al., "The impact of microRNAs on protein output," Nature, 455(7209): 64-71, 4 September 2008. [Whitehead Inst., Cambridge, MA; Howard Hughes Med. Inst., MIT, Cambridge; Harvard Med. Sch., Boston, MA] *343XS | 33 | 2 |
8 | H. Stefansson, et al., "Large recurrent microdeletions associated with schizophrenia," Nature, 455(7210): 232-7, 11 September 2008. [31 institutions worldwide] *346SZ | 33 | + |
9 | D.R. Bentley, et al., "Accurate whole genome sequencing using reversible terminator chemistry," Nature, 456(7218): 53-9, 6 November 2008. [7 European and U.S. institutions] *369DH | 30 | + |
10 | L.A. Hindorff, et al., "Potential etiologic and functional implications of genome-wide association loci for human diseases and traits," PNAS, 106(23): 9362-7, 9 June 2009. [NIH, Bethesda, MD] *456CN | 30 | + |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |
KEYWORDS: Antiangiogenesis, angiogenesis, cancer therapy, Judah Folkman, metastasis, Douglas Hanahan, Oriol Casanovas.