Cancer stem cells: in the line of fire.

Most tumours appear to contain a sub-population(s) of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The CSC model proposes that CSCs are at the apex of a hierarchically organized cell population, somewhat akin to normal tissue organization. Selection pressures may also facilitate the stochastic clonal expansion of sub-sets of cancer cells that may co-exist with CSCs and their progeny, moreover the trait of stemness may be more fluid than hitherto expected, and cells may switch between the stem and non-stem cell state. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In this review we discuss the basis of such resistance that highlights the roles of ABC transporters, aldehyde dehydrogenase (ALDH) activity, intracellular signalling pathways, the DNA damage response, hypoxia and proliferative quiescence as being significant determinants. In the light of such observations, we outline strategies for the successful eradication of CSCs, including targeting the self-renewal controlling pathways (Wnt, Notch and Hedgehog), ALDH activity and ABC transporters, blocking epithelial mesenchymal transition (EMT), differentiation therapy and niche targeting.

Postoperative hungry bone syndrome in patients with secondary hyperparathyroidism of renal origin.

BACKGROUND: Hungry bone syndrome (HBS) is a postoperative condition of severe hypocalcemia that can be seen in patients who have undergone parathyroidectomy (PTX) for secondary hyperparathyroidism (2HPT) of renal origin. This study examines HBS in patients after PTX for 2HPT. METHODS: Prospectively collected data was retrospectively reviewed in patients who underwent PTX for 2HPT of renal origin at a single institution. HBS was defined as the need for additional days of hospitalization or readmission for intravenous calcium supplementation due to clinical symptoms of hypocalcemia, including tingling, muscle spasms, and bone pain and/or immediate postoperative low serum calcium ≤7.5 mg/dl. RESULTS: Of 79 patients who underwent PTX for 2HPT, 27.8% (n = 22) experienced HBS. Young age (≤45 years, p = 0.02) was the only preoperative variable that predicted HBS. Most patients developed HBS within 18 h after surgery and required a prolonged hospital stay (19/22) compared to those requiring hospital readmission within the first 7 days (3/22). Initial postoperative serum calcium levels within 18 h of surgery were significantly lower in those patients who developed HBS (7.1 vs. 8.3 mg/dl, p = 0.001), and those patients also had a greater absolute decrease in serum calcium (2.8 vs. 3.5 mg/dl, p = 0.04). CONCLUSION: HBS develops in a significant proportion of patients generally within the first 18 h after subtotal PTX for 2HPT. The only identifiable preoperative risk factor for HBS was young age. Additionally, low initial calcium levels and greater absolute decrease in serum calcium may help identify those patients that will develop HBS requiring judicious calcium supplementation.

Cancer stem cells: problems for therapy?

Many, if not all, tumours contain a sub-population of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The symmetric division of CSCs is one mechanism enabling expansion in their numbers as tumours grow, while epithelial-mesenchymal transition (EMT) is an increasingly recognized mechanism to generate further CSCs endowed with a more invasive and metastatic phenotype. Putative CSCs are prospectively isolated using methods based on either a surface marker or an intracellular enzyme activity and then assessed by a 'sphere-forming' assay in non-adherent culture and/or by their ability to initiate new tumour growth when xenotransplanted into immunocompromised mice-hence, these cells are often referred to as tumour-propagating cells (TPCs). Cell sub-populations enriched for tumour-initiating ability have also been found in murine tumours, countering the argument that xenografting human cells merely select human cells with an ability to grow in mice. Cancer progression can be viewed as an evolutionary process that generates new/multiple clones with a fresh identity; this may be a major obstacle to successful cancer stem cell eradication if treatment targets only a single type of stem cell. In this review, we first briefly discuss evidence that cancer can originate from normal stem cells or closely related descendants. We then outline the attributes of CSCs and review studies in which they have been identified in various cancers. Finally, we discuss the implications of these findings for successful cancer therapies, concentrating on the self-renewal pathways (Wnt, Notch, and Hedgehog), aldehyde dehydrogenase activity, EMT, miRNAs, and other epigenetic modifiers as potential targets for therapeutic manipulation.

Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose?

Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. By comparison, the study of cancer stem cells is still in its infancy; so, unsurprisingly, there is great uncertainty as to the identity of these cells. Stem cell markers can be broadly categorized into molecular determinants of self-renewal, clonogenicity, multipotentiality, adherence to the niche, and longevity. This review assesses the utility of recognizing cancer stem cells by virtue of high expression of aldehyde dehydrogenases (ALDHs), probably significant determinants of cell survival through their ability to detoxify many potentially cytotoxic molecules, and contributing to drug resistance. Antibodies are available against the ALDH enzyme family, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these enzymes. Live cells expressing high ALDH activity are usually identified by the ALDEFLUOR kit and sorted by fluorescence activated cell sorting (FACS). For many human tumours, but notably breast cancer, cell selection based upon ALDH activity appears to be a useful marker for enriching for cells with tumour-initiating activity (presumed cancer stem cells) in immunodeficient mice, and indeed the frequency of so-called ALDH(bri) cells in many tumours can be an independent prognostic indicator.

Cell therapy for liver disease.

The clinical demand for whole organ transplantation for the treatment of end-stage liver disease far outstrips supply. As a result, research efforts have focused on hepatocyte therapies to support this scarce clinical resource, including the investigation of alternative cell sources, in particular bone marrow cells (BMCs). In animal models of metabolic liver disease, adopting strategies that provide a selective advantage for transplanted hepatocytes have proved to be highly effective in repopulating recipient livers, and the current relatively poor success rate of hepatocyte transplants in humans can be attributed to the lack of a clinically applicable procedure to induce a similar repopulation of the human liver. Autologous BMCs have been transplanted in a number of clinical trials involving patients with liver cirrhosis; modest improvements in liver health have been reported, but the mechanisms responsible for these effects are currently unknown. Transplanted hepatocytes can effectively repopulate a metabolically deficient liver, provided that a selective advantage exists for the donor cells. Some reports suggest that BMCs can differentiate into hepatocytes, but for the treatment of cirrhosis, the primary goal is to render the ingressing cells capable of degrading the excessive collagen associated with the disease. This review presents the progress and discusses some of the problems that need to be overcome in the field of cell transplantation for the treatment of metabolic and fibrogenic liver diseases.

Number crunching in the cancer stem cell market.

Like their normal counterparts, many tumours are thought to have a hierarchical organization, albeit a disorganized one. Accordingly, the concept of cancer stem cells has emerged, and that these cells are responsible for perpetuating tumour existence. Operationally, cancer stem cells are regarded as prospectively purified cells that are the most effective at tumour initiation in an in vivo assay, usually after xenotransplantation to NOD/SCID mice. The conventional wisdom is that such tumour-initiating cells are rare based upon having to xenotransplant large numbers of human tumour cells into immunodeficient mice to propagate the tumour, but new evidence indicates that perhaps these cells are not so rare, at least in malignant melanoma, if a supportive soil is provided for the transplanted cells along with further restriction of the murine host's immune response.

Nerve-sparing axillary dissection using the da Vinci Surgical System.

This is an initial report of a new method of axillary dissection via a periareolar incision and an 8 mm incision in the axilla with the da Vinci Surgical System. The 10x magnification and three-dimensional image, together with the versatility and precision of the robotic telemanipulators, has enabled us to perform nerve-sparing axillary dissection in four patients with invasive ductal carcinoma of the breast undergoing segmental (conservative) excision and level II axillary dissection. The time for the robotic axillary dissection ranged from 30 to 105 minutes (average 70.5 minutes). The average number of lymph nodes retrieved was 13 (11, 11, 13, and 17, respectively). Postoperatively all four patients recovered well and were discharged the next day. The robotic system can enhance the surgeon's ability by providing a high-definition, magnified, three-dimensional view of the operative field, intuitively controlled articulating instruments, and elimination of tremors; and it has potential benefits for the patient.

Laparoscopic-assisted axillary dissection in breast cancer surgery.

BACKGROUND: Significant morbidity such as pain, paresthesia, and arm stiffness has often been associated with axillary dissection for breast cancer. We report our experience of 30 patients with stage I and II invasive ductal carcinoma of the breast who underwent laparoscopic-assisted axillary dissection together with segmental mastectomy. METHODS: Tumours were situated in the upper or lower lateral quadrants only. In all cases, initial exposure for axillary dissection was performed through the breast periareolar incision. A 10-mm 30 degrees laparoscope was introduced through the breast incision to gain entry to the axilla. A separate stab incision in the lower aspect of the axilla was used for introduction of the 5-mm Harmonic shears (Ethicon Endo-Surgery, Inc, Cincinnati, OH). A grasping forceps was introduced through the main incision alongside the endoscope. Subsequent axillary dissection was performed laparoscopically, and the axillary content was removed through the breast incision. RESULTS: Average yield of lymph nodes was 15 (range 7 to 25). There were no intraoperative complications. Immediately postsurgery, all patients were able to fully mobilize the upper limb, facilitated by absence of an axillary scar. Patients also reported minimal pain, paresthesia, with no stiffness or frozen shoulder. CONCLUSION: Laparoscopic-assisted axillary dissection offers a safe and improved approach to the axilla, which can be incorporated into breast cancer surgery.