is also evidence to suggest that CSCs may be able to selectively resist many current cancer therapies, although this property has yet to be proven. For example, normal stem cells and metastatic cancer cells overexpress several common drug-resistance genes. As a result, breast CSCs express increased levels of several membrane proteins implicated in resistance to chemotherapy. These cells have also been shown to express signaling molecules such as Hedgehog and Bmi-1,44, which are essential for promoting self-renewal and proliferation of several types of stem cells. Moreover, experiments in cell lines from breast cancer and glioma have shown that CSCs (as identified by cell-surface markers) are more resistant to radiotherapy than their non-cancer stem cell counterparts. In the face of radiation, the CSCs appear to survive preferentially, to repair their damaged DNA more efficiently, and to begin the process of self-renewal.
These discoveries have led researchers to propose several avenues for treating cancer by targeting molecules involved in CSC renewal and proliferation pathways. Potential strategies include interfering with molecular pathways that increase drug resistance, targeting proteins that may sensitize cancer stem cells to radiation, or restraining the CSCs self-renewal capacity by modifying their cell differentiation capabilities. In each case, successful development of a therapy would require additional basic and clinical research. Researchers must characterize the CSCs associated with a given tumor type, identify relevant molecules to target, develop effective agents, and test the agents in preclinical models, such as in animals or cell lines. However, by targeting fundamental CSC cellular signaling processes, it is possible that a given treatment could be effective against multiple tumor types.
Existing cancer treatments have mostly been developed based on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals cannot provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study. The efficacy of cancer treatments is, in the initial stages of testing, often measured by the ablation fraction of tumor mass (fractional kill). As CSCs would form a very small proportion of the tumor, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells that form the bulk of the tumor, but are unable to generate new cells. A population of CSCs that gave rise to it could remain untouched and cause a relapse of the disease. Most of the studies that have identified human CSCs have used mouse xenograft assays and cells from only a small number of human tumor samples, making it difficult to draw firm conclusions. While these tumor-initiating cells have been described as being a rare class, several studies have found that the number of cells that can form tumors in these mouse experiments is actually quite large.
Zarish Umar
Independent Scholar
See Also: Brain Cancer; Colon Cancer; Fetal Stem Cells; Lung Cancer; Skin Cancer.
Further Readings
American Cancer Society. “Cancer Facts & Figures.” American Cancer Society (2008).
Ignatova, T. N., V. G. Kukekov, E. D. Laywell, et al. “Human Cortical Glial Tumors Contain Neural Stem-Like Cells Expressing Astroglial and Neuronal Markers in Vitro.” Glia, v.39/3 (2002).
National Institutes of Health. Stem Cells Basics. Bel Air, CA: University Press of the Pacific, 2004.
National Institutes of Health. Stem Cells: Scientific Progress and Future Research Directions. Bel Air, CA: University Press of the Pacific, 2004.
Scadden, David T., et al. “Overview of Stem Cells.” UpToDate (n.d.), http://www.uptodate.com/contents/overview-of-stem-cells.
Cartilage, Tendons, and Ligaments: Cell Types Composing the Tissue
Cartilage, Tendons, and Ligaments: Cell Types Composing the Tissue
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Cartilage, Tendons, and Ligaments: Cell Types Composing the Tissue
Cartilage is a firm and flexible type of connective tissue consisting of cells and intracellular fibers in a gel-like material. It has a smooth and resilient surface and a weight-bearing capacity exceeded only by that of bone. It is composed of cells called chondroblasts and chondrocytes and extracellular matrix. The matrix is made up of aggrecan (10 percent), water (75 percent), and a mix of collagen fibers and other constituents.
There are three types of cartilage: elastic cartilage, hyaline cartilage, and fibrocartilage. They differ mostly in the type of fibers they contain. Elastic cartilage contains some elastin in its intercellular substance. It is found in most areas such as the ear, where some flexibility is required. Fibrocartilage has intermediate characteristics between hyaline cartilage and dense connective tissue. It is primarily found in the intervertebral disks and in the symphysis pubis. Finally, hyaline cartilage is the most abundant type of cartilage and forms most of the fetal skeleton. In the adults, it forms the costal cartilages and respiratory, articular, and epiphyseal cartilages. The free surfaces of most hyaline cartilage are covered by a layer of fibrous connective tissue called the perichondrium:
Hyaline: most common, glassy appearance
Elastic: elastic plus collagen fibers
Fibrocartilage: parallel bundles of collagen fibers, least number of chondrocytes
Chondrocytes, being the only type of cells present, are found in healthy cartilage. The progenitor of chondrocytes arises in the bone marrow in the form of stem cells. When stem cells differentiate into cartilage cells, they are initially chondroblasts. These secrete chondrin, the substance in cartilage responsible for building and repairing of the tissue. The extracellular matrix, mainly collagen and proteoglycans, is also secreted by chondroblasts. These precursor cells are found in the outer layer of cartilage. The secreted matrix and fibers entrap the chondroblasts and eventually mature into cells called chondrocytes. These cells are located in lacunae, which are surrounded by an uncalcified gel-like intercellular matrix of collagen fibers and ground substance.
Lacunae consist of rounder chondrocytes daughter cells that remain close together in groups, forming nests of 2 to 4 cells. The active cells are large secretary cells with basophilic cytoplasm and abundant rough endoplasmic reticulum. The number of cells found in the cartilage tissue determines how bendy the structure is. They perform a number of functions, including facilitating the exchange of fluids through gelatinous layers. Since cartilage is an avascular structure, it relies on this exchange to receive nutrients and express waste materials. Chondrocytes undergo terminal differentiation during endochondral ossification. The cell exhibits major phenotypic changes, predominantly hypertrophy.
Under normal circumstances, wearing of cartilage is replaced and repaired by the chondrocytes. However, in some conditions the cartilage damage is so extensive that surgical intervention must be used to correct the problem. Transplants with patient’s own cells or a donor’s cell preparation can also be used to address problems with cartilage.
Tendons and Ligaments
Tendons and ligaments are specialized forms of dense fibrous connective tissue. They are composed of fibroblasts embedded in extracellular matrix (ECM) of ground substance and connective tissue fibers. Type 1 collagen is the main constituent in both tissues.
