Cancer Stem Cells and Differentiation Therapy

Abstract

Cancers arise from stem cells in adult tissues and the cells that make up a cancer reflect the same stem cell → progeny → differentiation progression observed in normal tissues. All adult tissues are made up of lineages of cells consisting of tissue stem cells and their progeny (transit-amplifying cells and terminally differentiated cells); the number of new cells produced in normal tissue lineages roughly equals the number of old cells that die. Cancers result from maturation arrest of this process, resulting in continued proliferation of cells and a failure to differentiate and die. The biological behavior, morphological appearance, and clinical course of a cancer depend on the stage of maturation at which the genetic lesion is activated. This review makes a comparison of cancer cells to embryonic stem cells and to adult tis sue stem cells while addressing two basic questions: (1) Where do cancers come from?, and (2) How do cancers grow? The answers to these questions are critical to the development of approaches to the detection, prevention, and treatment of cancer.

Osteosarcoma Cells Differentiate into Phenotypes from all Three Dermal Layers

“…As we did not test all osteosarcomas, we cannot be certain that, in reality, all sarcomas contain multipotent stem cells. However, if this is the case, treatment of osteosarcomas with exogenous differentiation agents may cause the small fraction of multipotent, cancer stem cells in the osteosarcoma to differentiate, thus causing them to cease proliferating [51] and providing a new treatment in the armamentarium against osteosarcomas.…”

“…Stem cells are defined by two parameters: extended proliferation potential and the ability to differentiate into one or more phenotypes [3,4,6,56]. Normal adult tissue contains multipotent adult stem cells that retain the ability to differentiate into several mesodermal phenotypes from all three dermal lineages [32,50] and progenitor stem cells that have the limited differentiation capability of forming only the cell types in that tissue [51]. Tumors are thought to arise from clonal expansion of a progenitor cell to a group of cells consisting of partially or wholly differentiated cells that no longer divide and a small percentage of cells that continue to divide -cancer stem cells [11,15,16,42,51,53,59].…”

“…Normal adult tissue contains multipotent adult stem cells that retain the ability to differentiate into several mesodermal phenotypes from all three dermal lineages [32,50] and progenitor stem cells that have the limited differentiation capability of forming only the cell types in that tissue [51]. Tumors are thought to arise from clonal expansion of a progenitor cell to a group of cells consisting of partially or wholly differentiated cells that no longer divide and a small percentage of cells that continue to divide -cancer stem cells [11,15,16,42,51,53,59]. This hypothesis has been supported by the observations that fully differentiated malignant neoplasms express a distinguishable phenotype of that particular tissue [5,14,15,33] and that undifferentiated neoplasms are monoclonal in origin [5,7,16,34].…”

Differentiation Therapy with Cancer Stem Cells

“…Perhaps the model proposed by Stewart Sell may give a more thorough picture of CSCs in cancer initiation and promotion [5]. The idea is that the most primitive stem cells normally do not divide in adult tissues, and there is asymmetric division of transit-amplifying cells, so that one daughter cell remains a progenitor cell whereas the other differentiates.…”

“…To this point, differentiation therapy has been proposed to induce terminal differentiation of the cancer stem or progenitor cells so that active proliferation and chemoresistance can be suppressed. The therapy has been encouraged by some preclinical and clinical outcomes including inhibiting glioblastoma expansion with BMP-4 [6], and in treating acute promyelocytic leukemia with retinoic acids (vitamin A analogs) to remove the maturation block [5]. The proposed study is aimed at preliminarily validating the concept described above.…”