Contrary to a long-standing assumption that blood vessel cells in healthy tissues and those associated with tumors are similar, a new study unequivocally demonstrates that tumor blood vessel cells are far from normal.  The research, published by Cell Press in the September issue of the journal Cancer Cell, identifies tumor-specific blood vessel cells that are atypically stem cell-like and have the potential to differentiate into cartilageor bone-like tissues.

Although it has been known for some time that tumors can be eradicated in mice by targeting their blood supply, very little is known about the biology of the endothelial cells that line tumor blood vessels (TECs).  “A primary assumption of antiangiogenesis therapy is that TECs are normal and derived from nearby, preexisting vessels,” explains senior author Dr. Michael Klagsbrun from Children’s Hospital Boston and Harvard Medical School.  “However, we and other groups have shown that there are several key differences between normal and tumor endothelium.”

Dr. Klagsbrun and lead author Dr. Andrew Dudley isolated TECs from mice that spontaneously develop prostate tumors very similar to human prostate cancers.  The researchers found that the TECs were multipotent, meaning that they were not fully mature and had the potential to differentiate into multiple different types of cells.  The isolated TECs differentiated to form cartilageand bone-like tissues.  “These results suggest that TECs possess a stem/progenitor cell property that distinguishes them from Ecs throughout the normal vasculature and undergo atypical differentiation,” explains Dr. Klagsbrun.

The researchers went on to demonstrate blood vessel calcification in human and mouse prostate tumor specimens.  This bone-like calcification has also been described in diseased blood vessels and is likely to have clinical significance in prostate cancer.  “It is possible that calcification of tumor blood vessels could impair blood flow or enable tumor cell entry into the bloodstream, facilitating metastasis,” offers Dr. Klagsbrun.  “Further, the expression of bone-specific proteins in prostate tumor cells may enable their survival once they reach the bone microenvironment.”

Additional research is required to determine how the atypical properties of TECs are associated with the tortuous, leaky vessels characteristic of tumors and whether vascular calcification does indeed encourage tumor cell metastasis.  It is also possible that vascular calcification, which is easily discernible histologically, may be a useful diagnostic criterion.

Although prostate cancer is the second most common cause of death from cancer in the US, it is not the tumor in the prostate that usually causes death.  Rather, death mainly occurs as a result of the tumor spreading to the bones, where it is known as an osteoblastic bone metastasis.  Treatments that deprive the tumor of male sex hormones (androgens) are usually effective, but only briefly as the tumors typically develop the ability to grow in the absence of androgens and the diseases progresses.  New data, generated using two prostate cancer cell lines that lack expression of androgen receptors and that were derived from the bones of an individual with osteoblastic bone metastases, by Nora Navone and colleagues, at The University of Texas MD Anderson Cancer Center, Houston, have provided new insight into the mechanisms by which prostate cancer osteoblastic bone metastases progress.

The androgen receptor–negative prostate cancer cell lines generated by the authors grew when transplanted into immunocompromised mice and generated osteoblastic bone metastases.  A protein known as FGF9 was found to be expressed at higher levels in these cells lines than in other bone-derived prostate cancer cells and induced bone formation in an in vitro organ culture assay.  Further, as blocking FGF9 reduced the osteoblastic bone metastases in mice transplanted with the cell lines and FGF9 was found to be expressed in all human prostate cancer osteoblastic bone metastases analyzed, the authors suggest that FGF9 has an important role in prostate cancer progression to osteoblastic bone metastases.  The cells lines generated are also likely to be an important preclinical model for researchers developing therapeutics for osteoblastic bone metastases in individuals with prostate cancer.

As tumors progress they develop ways to escape recognition and attack by cells of the immune system. However, the mechanisms by which tumors modify the immune system have not been clearly determined. New insight into the way in which chronic lymphocytic leukemia (CLL) cells limit immune cell attack has now been provided by John Gribben and colleagues, at Barts and The London School of Medicine, United Kingdom.

For immune cells known as CD4+ and CD8+ T cells to become activated they must contact other cells known as APCs. The area of contact is known as the immunological synapse and it is highly organized. In the study, CD4+ and CD8+ T cells from patients with CLL were found to exhibit defective immunological synapse formation with APCs. Further, if CD4+ and CD8+ T cells from healthy individuals were cultured with CLL APCs, they also showed defective immunological synapse formation. As treatment with an immune system–modifying drug improved immunological synapse formation, the authors suggest that approaches to overcoming immunological synapse defects might improve the efficacy of new ways to treat cancer that are currently being developed and that are based on enhancing the antitumor activity of CD4+ and CD8+ T cells.

Primary tumors can encourage the growth of stray cancer cells lurking elsewhere in the body that otherwise may not have amounted to much, according to a new study in the June 13 issue of the journal Cell, a publication of Cell Press. As people age, most may have such indolent cancer cells given the sheer number of cells in the body, although their rarity makes them impossible to detect, the researchers said.

The primary tumors under study, which were derived from human breast cancers, seem to “instigate” the growth of other cancers by mobilizing bone marrow cells, which then feed the secondary tumors’ growth, they report.

One key to the process is the secretion of a substance known as osteopontin by the instigating tumor, a finding that may have therapeutic implications. Indeed, the researchers noted that osteopontin is present at elevated levels in women with metastatic breast cancer, supporting the notion that the new findings may hold clinical significance.

” If metastases depend on stimulation by primary tumors, interception of the signal through neutralizing antibodies” might block cancer spread, said Robert Weinberg of the Massachusetts Institute of Technology. “That’s still speculative, but it’s an interesting idea to ponder,” he added, noting that treatments today don’t specifically target metastases, which are responsible for the vast majority of cancer deaths.

The researchers noted that while the effects of the tumor microenvironment has been much studied, much less was known about how the systemic environment in the body contributes to tumor growth. Several earlier reports had shown that assorted bone marrow-derived cells can be incorporated to various extents into the supportive framework, or stroma, of tumors. However, it wasn’t clear whether tumors actively recruit stromal cells by directly perturbing other cell reservoirs, such as the bone marrow, or whether tumors are just passive recipients of stromal cell precursors that normally circulate throughout the body.

In the new study, the researchers injected “instigating” human tumor cells into mice along with indolent “responding” cancer cells also derived from humans. Those indolent cells formed vigorously growing tumors only in the presence of the instigating tumor cells, they reported. They found further evidence that the instigating tumor somehow perturbs the makeup of the bone marrow, although Weinberg said they don’t really know how that happens. They also show that osteopontin is necessary to the process, but that it does not act alone.

Finally, they showed that the same instigation process can encourage the growth of disseminated metastatic cancer cells. Instigating breast tumors in the mice also drove the growth of implanted fragments of human colon tumors, a finding that they said shows the generality of the physiologic signaling.

Nonetheless, the researchers said they don’t yet know how universal this systemic instigation of tumor growth might be. Still, the findings challenge the “prevailing view that primary tumors suppress the growth of derived metastases,” Weinberg said. “We argue they can foster cancer’s spread by activating bone marrow that is then recruited by distant metastases.”

The findings also have important implications for the preclinical study of human cancers, Weinberg emphasized.

” The ability of instigating tumors to foster the growth of a human colon tumor surgical specimen underscores the powers of systemic instigation,” the researchers wrote. “Indeed, to our knowledge, methods to expedite the growth of human tumor surgical specimens in vivo have not been previously described. These results suggest that the presently described procedure can be used to study aspects of human tumor biology that would otherwise be difficult if not impossible to study.

” In the longer term, identification of additional tumor-derived factors that perturb the host systemic environment in one way or another may allow one to predict the effects that a given primary tumor type has on the outgrowth of indolent cancer cells that have disseminated to distant sites.”

The investigational chemotherapeutic agent eribulin mesylate (E7389) demonstrated activity in a heavily pretreated population of women with locally advanced or metastatic breast cancer, according to results of a multi-center Phase II clinical trial. The study also suggests that eribulin mesylate has a manageable tolerability profile, with a low incidence of Grade 3 (severe) and no Grade 4 (disabling or life-threatening) neuropathy. These data (abstract #1084) will be presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) on Monday, June 2 from 2 to 6 p.m. at S Hall A1 of McCormick Place.¡°The anti-tumor activity of eribulin mesylate, as observed in this study, is encouraging, given the limited treatment options for women with advanced breast cancer who have previously received multiple lines of therapy,¡± said lead investigator Linda T. Vahdat, MD, of Weill Cornell Medical College in New York. ¡°The subjects in this trial had received a median of four prior chemotherapy regimens that included an anthracycline, a taxane and capecitabine.¡±

About Study 211 Study 211 is a Phase II, open-label, single-arm study evaluating the efficacy and safety of eribulin mesylate in patients with locally advanced or metastatic breast cancer who had received an anthracycline, a taxane and capecitabine as prior therapy, and who were refractory to their last chemotherapy regimen, as documented by progression on or within six months of that therapy.

Of 299 patients enrolled in the study, 291 were treated with eribulin mesylate. The median age of those patients was 56 years (range: 26-80 years). Eribulin mesylate was administered at a dose of 1.4mg/m2 as a 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle. Patients received a median of four cycles of eribulin mesylate (range 1-27). No premedication to prevent hypersensitivity was required.

Two-hundred sixty-nine patients met the key inclusion criteria. In patients who received a median of four cycles of eribulin mesylate, Overall Response Rate (ORR) by Independent Review (IR) was 9.3% (all Partial Responses (PR); 95% confidence interval [CI]: 6.1%-13.4%). Investigator-assessed ORR was 14.1% (1 CR; 95% CI: 10.2%-18.9%). Nearly half (46.5%) the patients had stable disease (SD) after treatment with eribulin mesylate. The clinical benefit rate (CBR, defined as CR+PR+SD ¡Ý6 months) was 17.1% (95% CI: 12.8%-22.1%).

The median duration of response was 4.2 months (126 days, range: 42 -258 days; 95% CI: 86-147). Median progression-free survival (PFS) was 2.6 months (79 days, range: 1*-397 days), and the median overall survival (OS) rate was 10.3 months (315 days, range: 19-604 days; 95% CI: 279-350). The six-month PFS and OS rates were 16.0% (95% CI: 8.6-17.0) and 72.3%, respectively (95% CI: 66.9-77.6).

The safety analysis included all 291 patients who received treatment with eribulin mesylate. Patients with up to Grade 2 peripheral neuropathy were included in the study. The most frequently reported Grade 3 (severe) or Grade 4 (disabling or life- threatening) adverse events were neutropenia (a decrease in the number of granular white blood cells, 54%); febrile neutropenia, 5.5%, leukopenia (low white blood cell count, 14%), and weakness/fatigue (10%; no Grade 4 events). Grade 3 peripheral neuropathy (a functional disturbance or damage to nerves outside the brain and spinal cord) was reported in 5.5% of patients. No Grade 4 peripheral neuropathy events were reported. No correlation was seen between Grade 2 peripheral neuropathy and deterioration.

“In this study, eribulin mesylate appeared to have an acceptable tolerability profile, particularly with regard to the low incidence of peripheral neuropathy,” noted Vahdat. “None of the reported cases of neuropathy were disabling, suggesting that eribulin mesylate, if approved, may be a useful addition to the treatment armamentarium for advanced breast cancer.”