In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution

Abstract

Villadsen R. In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution. APMIS 2005;113:903-21. By deliberate analogy with the well-established concept of hematopoiesis, the term ''mammopoiesis'' is occasionally used to describe the development of the different cellular lineages and functional units in the mammary gland. The use of this term signifies a strong bias towards the idea that tissue homeostasis during mammary development, pregnancy, lactation and involution is brought about by the action of somatic stem cells characterized by longevity and multipotency. The progenies hereof eventually differentiate into structurally and functionally well-defined ductal-lobular units. During the past two decades evidence of such a notion in the mouse has developed from being largely circumstantial based on non-clonal in vivo experiments to a quite elaborate characterization of individual candidate stem cells by a number of different properties. Within tumor biology this has led to a renaissance of the concept of tumors as caricatures of tissue renewal. Thus, recent molecular classification of breast cancer based on genome wide expression analysis operates with different subtypes with specific reference to the normal luminal epithelial and myoepithelial/basal lineages in the breast. Apparently some tumors are lineage restricted and others differentiate more broadly as if they have preserved some stem-like properties. This holds promise for the existence of a stem cell hierarchy, the understanding of which may prove to be instrumental in further dissecting the histogenesis of breast cancer evolution. Most attention has been devoted to the question of different cellular origins of cancer subtypes and different susceptibilities of possible stem cells to gain or loss of oncogenes and tumor suppressor genes, respectively. Invaluable progress has been made over the past two decades in culture technology not only in terms of population doubling and clonal growth, but also the availability of lineage specific markers, cell sorting, and three-dimensional functional assays for tissue specific morphogenesis. Transcriptional profiling of stem cell zones has unraveled a hitherto unknown preservation of signaling pathways for maintenance of stem cell properties across tissue boundaries and species. Somatic stem cells have therefore been narrowed down to specific anatomic locations not only in rapidly renewing tissues such as skin and skin derivatives, but also in tissues with slower turnover times, such as lung, kidney and prostate. It is therefore now possible to integrate this information in a search for similar cells within the breast. Even if cell turnover after birth is provided exclusively by dividing lineage-restricted cells, more information about the robustness of breast differentiation programs during tumor progression is still very much required. Complete knowledge of the primary cell of origin of breast cancer and the mechanisms that influence differentiation programs during tum...

Progenitor stem cell marker expression by pulmonary carcinomas

“…15 This study was based on immunohistochemistry of archival paraffin-embedded tissue, which limits our ability to include other markers associated with stem cells, such as those used in the detection of antigens by flow cytometry of dissociated tumor cells or cell lines. [30][31][32][33][34] Immunohistochemistry may have also limited our ability to detect antigens that are expressed in a small number of cells. This may be particularly relevant to the low detection of antigen, such as CD133 and CD34.…”

Breast Tumor Heterogeneity: Cancer Stem Cells or Clonal Evolution?

“…Also, according to the cancer stem cell hypothesis, tumor progression is a result of the metastatic spread of these cells, and cancer recurrence is caused by their resistance to therapy. 10,[14][15][16][17][18][19][20][21][22][23][24][25][26] Supporting evidence. The idea that cancers originate from rare stem cells is a long-standing one, first proposed over a century ago by Cohnheim,27 that is supported by many general observations of biology.…”

“…In particular, injecting cells into mice does not mimic the numerous effects that the human cancer cell microenvironment is believed to have on solid tumor initiation and progression. 1,[11][12][17][18]35,53,71 Furthermore, since the mice used are immunocompromised, effects of an immune system are not measured. Additionally, the efficiency of tumor transplantation in mice and other animal models depends on the location of transplantation.…”

“…49 In addition, most breast cancers arise within a relatively short segment of terminal ductules that might be the location of normal stem cells. 18 Finally, a marker associated with normal breast stem cells, CD44, was used to identify breast cancer stem cells in 2003. These were the first solid tumor cancer stem cells to be isolated.…”

Mutant TNF-α negatively regulates human breast cancer stem cells from MCF7 in vitro

“…Self-renewal, one of the key properties of stem cells, refers to their ability to divide unevenly. 29 Normal stem cells are rare cells within organs with the ability to self-renew and give rise to all types of cells within the organ to drive organogenesis. Stem cells divide asymmetrically producing two daughter cells-one is a new stem cell and the other a progenitor cell which has the ability for differentiation and proliferation, but with a little or no capability for self-renewal.…”