A. C. Hirbe et al. from Washington University School of Medicine reported in the August 20th online edition of PNAS that disruption of the expression of the chemokine receptor, CXCR4, in hematopoietic cells results in an increase in osteoclasts and bone tumor growth. CXCR4 is known to be expressed in both hematopoietic and tumor cells. The expression of the receptor is associated with homing for CD34+ cells and metastasis on tumor cells. With a bone metastasis animal model, the investigators found that reconstitution with CXCR4-/- hematopoietic cells resulted in an increase in bone resorption concomitant with an increase in bone tumor growth in these animals. The researchers demonstrated that they could abrograte tumor growth with an inhibitor, zoledronic acid, which prevents osteoclastogenesis. The authors concluded that "disruption of CXCR4 enhances osteoclastogenesis and its inhibition may enhance skeletal tumor burden by increasing osteoclast activity."

Investigators from the Whitehead Institute at MIT reported in the August 14th issue of Cancer Cell on the results of their study in delineating the phenotypes of normal human mammary epithelial cells being transformed in vitro into different neoplastic phenotypes. With a new cultivation medium, the researchers were able to generate from normal human mammary epithelial cells two unique populations of neoplastic cells in vitro. It was reported that one subpopulation of human malignant epithelial cells (HMECs) yielded a population of cells with a squamous cell carcinoma phenotype. Another subpopulation of transformed cells (BPECs) resembled human breast adenocarcinomas. The investigators found these BPECs were highly tumorigenic as xenografts and 10⁴-fold more in their tumorigenicity than HMECs. The BPMECs were also metastatic as oppose to the HMECs which were non-metastatic. The authors suggested that the BPMECs were a subpopulation of human breast mammary cells which were transformed into cancer-initiating or cancer stem cells. They also surmised that the HMECs gave rise to cells that formed the bulk of the tumor.

In the August 9th online edition of Stem Cells, I. Avital et al. from the National Cancer Institute reported their findings in a study involving 4 male patients who developed solid organ cancers (lung adenocarcinoma, larygneal squamous cell carcinoma, glioblastoma, and Kaposi sarcoma). These male cancer patients received an allogeneic bone marrow transplant (ABMT) following myeloablation by total body irradiation. The bone marrow-derived cells were from female donors. The investigators found that 2.5-6% of malignant cells comprising the tumors were of donor origin. The authors noted that the compiled data suggested that human bone marrow-derived stem cells have a role in solid organ cancer's carcinogenesis. They also pointed out that, "however, the nature of this role is yet to be defined."

With the heightened interest in cancer stem cells, a new therapeutic approach suggested by many investigators is to develop a treatment regimen that terminally differentiates these cancer stem cells in lieu of trying to eliminate them with toxic chemotherapeutic agents. For example, during the 2003 Annual Meeting of the American Society of Hematology (ASH), Dr. Zhen-Yi Wang from the Shanghai Institute of Hematology received the Han-Wasserman award for his ground-breaking work on using all-trans-retinoic acid and arsenic trioxide to treat patients with acute promyelocytic leukemia (APL). This differentiation regimen was found to have a 90% cure rate in patients diagnosis with this form of leukemia. Similarly, Y. Li et al. from the Sun Yat-Sen University in China reported in the August 6th online edition of PNAS that they were able to use cholera toxin to induce differentiation in vitro of both rat and human malignant glioma cells. The cholera toxin was found to induce accumulation of cAMP and glial fibrillary acid protein (GFAP) in the cell cultures. The cholera toxin was also found to inhibit cellular proliferation by preventing cells from progressing from the G¹ to S phase of the cell cycle. This inhibition in the cell cycle appears to be the result of the toxin preventing the expression of the cell-cycle regulatory proteins D1 and Cdk2 along with overexpression of the cell-cycle inhibitory proteins p21^Cip1 and p27^Kip1. The investigators demonstrated that inhibiting protein kinase A activity resulted in abrogation of the of the cAMP-responsive element (CREB) and this led to suppressed differentiation of the gliomas. The authors concluded that differentiation therapy through activation of the PKA/CREB pathway may be "a key requisite factor in glioma differentiation."

The interplay between the microenvironment in the stem cell niche and the stem cells residing in a particular tissue compartment is an important parameter for determining the stem cell's fate with respect to self-renewal, asymmetric cell division, proliferation, commitment, and differentiation to a particular tissue lineage. The microenvironment is also important in cancers, particularly in modulating cancer stem cells in a particular tumor. In this regard, Wu et al. from the University of Rochester reported in the July 25th online edition of PNAS on a study of the role of prostate stromal cells in modulating organogenesis in mice. The investigators found that mice lacking the epithelial androgen receptor had prostates that were less differentiated concomitant with in an increase in hyperproliferative tissues compared to the wild-type litter mates. Although the investigators found normal levels of circulating testosterone and the mutant mice were fertile, these mice lacked the ability to develop into a mature prostate. When the gene encoding the androgen receptor was transfected into these deficient mice, the researchers found that the transfected mice had normal prostate glands as they reached maturity. The authors concluded that their data suggested that the prostatic "epithelial androgen receptor plays an important role in the homeostasis of the prostate gland."

Finnish scientists from the University of Helsinki, M Taskinen et al., reported in the July 15th issue of Cancer the results of their study on children and adolescents (median age 10 years) with leukemia following allogeneic bone marrow transplants. In the 44-patient study, the investigators found that 16 patients (36%) had lower bone mineral density (BMD) with a higher incidence occurring in postpubertal subjects. Bone thinning in the hips was particularly noted in prepubertal children. It was also noted that 9 patients (20%) patients had vertebral compression fractures, which were asymptomatic in 7 patients. The investigators concluded that leukemic children who had received an allogeneic bone marrow transplant need to be carefully monitored and administered drugs that enhance bone strength and growth. (The mechanism that gives rise to suppression/destruction of osteoclasts and osteoblasts. One obvious question is whether the allogeneic transplant was generating in the recipient T cells mediating a cellular immune response to either the osteoblast or osteoclast?)