Abstract
Prostate cancer cells are heterogeneous in their tumorigenicity. For example, the side population cells isolated from LAPC9 xenografts are 100 to 1,000 times more tumorigenic than the corresponding non-side population cells. Highly purified CD44(+) prostate cancer cells from several xenografts are also enriched in prostate cancer stem/progenitor cells. Because the CD44(+) prostate cancer cell population is still heterogeneous, we wonder whether we could further enrich for tumorigenic prostate cancer cells in this population using other markers. Integrin alpha2beta1 has been proposed to mark a population of normal human prostate stem cells. Therefore, we first asked whether the alpha2beta1(+/hi) cells in prostate tumors might also represent prostate cancer stem cells. Highly purified (> or =98%) alpha2beta1(+/hi) cells from three human xenograft tumors, Du145, LAPC4, and LAPC9, show higher clonal and clonogenic potential than the alpha2beta1(-/lo) cells in vitro. However, when injected into the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse prostate or s.c., the alpha2beta1(+/hi) prostate cancer cells are no more tumorigenic than the alpha2beta1(-/lo) cells. Immunofluorescence studies reveal that CD44 and alpha2beta1 identify an overlapping and inclusive population of prostate cancer cells in that approximately 70% of alpha2beta1(+/hi) cells are CD44(+) and 20% to 30% of CD44(+) cells are distributed in the alpha2beta1(-/lo) cell population. Subsequently, we sorted out CD44(+)alpha2beta1(+/hi), CD44(+)alpha2beta1(-/lo), CD44(-)alpha2beta1(+/hi), and CD44(-)alpha2beta1(-/lo) cells from LAPC9 tumors and carried out tumorigenicity experiments. The results revealed a hierarchy in tumorigenic potential in the order of CD44(+)alpha2beta1(+/hi) approximately CD44(+)alpha2beta1(-/lo) > CD44(-)alpha2beta1(+/hi) >> CD44(-)alpha2beta1(-/lo). These observations together suggest that prostate cancer cells are organized as a hierarchy.
Highlights
The cancer stem cell model posits that not all cells in a tumor are equal, and that tumor-initiating cells are a rare subset with a distinct phenotype (1, 2)
A2B1 expression correlates with malignancy in prostate cancer cell lines and xenografts. a2h1, an integrin expressed in the human prostate (25) and mediating adhesion to collagen I/IV and laminin I (26), has been proposed to identify normal human prostate stem cells (21)
To determine whether prostate cancer cells expressing high levels of a2h1 in prostate tumors might represent prostate cancer stem/progenitor cells, we examined its expression in the commonly used prostate cancer cell lines LNCaP, Du145, PC3, and PPC-1 (27), as well as in the LAPC4 and LAPC9 xenograft tumors (10), using a monoclonal antibody (mAb) against the a2 subunit
Summary
The cancer stem cell model posits that not all cells in a tumor are equal, and that tumor-initiating cells are a rare subset with a distinct phenotype (1, 2). This hierarchical model helps explain why most tumors are heterogeneous they have a clonal origin; why it is often difficult to establish a permanent cell line from primary tumors; and why it takes tens of thousands of cancer cells. To completely eradicate a tumor and prevent recurrence, it is imperative that cancer stem cells be targeted
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