• Anne Forde

• Stem-like Cells Found in Retinoblastoma

Zhong et al., pp. 2125–2131

It is thought that only a minority of cells within any tumor have the ability to self-renew. In the context of retinoblastoma (RB), the consensus view is that RB cells originate from retinal stem cells (RSC) or multipotent primitive retinoblasts. There is, however, no direct evidence that tumorigenic RSCs actually exist within RBs.

Previously, Zhong et al. had successfully cultivated stem-like cells from human RBs. In this report they have taken the results a step further by investigating whether these retinal stem-like cells (RSLCs) have the potential to reproduce the parental tumor in vivo. Using tumor tissues from eight patients with either differentiated or nondifferentiated RB, primary cell cultures were generated under conditions that favored stem cell growth. All tumor-derived cultures developed nonadherent neurospheres that could be passaged many times.

These cells were found to be capable of self-renewal and expressed neural stem cell markers such as pax6, nestin and Bmi-1. RSLCs also exhibited an impressive degree of multipotentiality, forming neurons and glial cells – among others – though they fell short of the full cellular repertoire of RSCs.

After intraocular (I.O.) injection of four of the RB primary cultures into NOD/SCID mice, the mice developed tumors within 2–12 weeks. Interestingly, these xenograft tumors were very similar to their parental tumor cells. To further confirm that these xenografts contain RSLCs, single tumor cells were isolated from the xenograft tumors and reinjected I.O. into new animals, which in turn developed RB-like tumors.

These findings strongly suggest that RB derives from RSLCs. In addition to furthering our understanding of RB tumorigenesis, this model could be useful in developing new therapeutic approaches for the disease.

• Biomarkers for Prostate Cancer Prediction

Vickers et al., pp. 2212–2217

Total prostate specific antigen (tPSA) levels can be raised in benign prostate disease, particularly in older patients, complicating its usefulness as a predictor of prostate cancer. Previous studies have shown that levels of human kallikrein-2 (hK2) and the ratio of free to total PSA (%fPSA) may also reflect underlying prostate malignancy. In this study, Vickers et al., wanted to determine whether the combination of these biomarkers could offer a better means of detecting prostate cancer and whether the biomarkers vary as a function of age.

Using blood samples from a very large (13,600) cohort of men between the ages of 44 and 50 and 59 and 61 and data from the Swedish Cancer Registry, the authors determined odds ratios and the predictive probability of the various biomarkers in over 500 prostate cancer patients. They found that the predictive value of tPSA is inversely associated with age but not with time of diagnosis. The predictive value of %fPSA combined with hK2 was inversely related to the time of diagnosis but not modified by age. Using tPSA, %fPSA and hK2 compared to tPSA alone enhanced prediction levels in older patients but not younger ones.

The results from this study importantly show the value of screening younger men (<50) for PSA and that combined biomarker testing may be needed to detect prostate malignancy more accurately in older subjects.

• Second Malignancies After Childhood Cancer

Inskip et al., pp. 2233–2240

Mortalities associated with childhood cancers have decreased over the last few decades. However, the aggressive nature of the treatments means that patients are subsequently at risk of developing new primary cancers.

Setting up a large-scale follow-up of childhood cancer survivors is not an easy task. In this report, Inskip et al. use a US population-based cancer registry — SEER – which contains data on nearly 26,000 childhood cancer survivors from 1973–2002, to determine new malignancy risk in childhood cancer patients.

Using observed to expected ratios and regression analysis, the cancer survivors were found to have an almost 6-fold increased risk of developing a new primary cancer compared to the general population. The degree of risk and nature of the second cancer was highly dependent on the first type of cancer the patient had suffered from. Hodgkin lymphoma (HL), retinoblastoma, primitive neuroectodermal tumor and Ewing sarcoma were the cancers associated with the highest risk of developing a second primary cancer. The most likely subsequent cancers were female breast, CNS, bone, thyroid, soft tissue, melanoma and acute nonlymphocytic leukemia (ANLL). The mode of original cancer treatment also had an influence on subsequent cancer development. Patients who had received radiotherapy were more likely to develop a solid tumor, whereas patients treated with chemotherapy were at higher risk of developing ANLL.

This thorough study gives a comprehensive analysis of the new malignancy risks facing survivors of childhood cancer. This perspective and future follow-up studies will be important to help monitor patients and evaluate the risks associated with changing cancer treatments.