Abstract
Multiple cancer cell types are found in prostate tumors. They are either luminal-like adenocarcinoma or less luminal-like and more stem-like non-adenocarcinoma and small cell carcinoma. These types are lineage related through differentiation. Loss of cancer differentiation from luminal-like to stem-like is mediated by the activation of stem cell transcription factors (scTF) such as LIN28A, NANOG, POU5F1 and SOX2. scTF expression leads to down-regulation of β2-microglobulin (B2M). Thus, cancer cells can change from the scT˜FB2MhiscTF˜B2Mhi<math><mrow><mtext>scT</mtext><mover><mtext>F</mtext><mo>˜</mo></mover><mtext>B</mtext><mn>2</mn><msup><mtext>M</mtext><mi>hi</mi></msup></mrow></math> phenotype of differentiated to that of scTF˙B2MloscTF˙B2Mlo<math><mrow><mtext>scT</mtext><munder><mtext>F</mtext><mo>˙</mo></munder><mtext>B</mtext><mn>2</mn><msup><mtext>M</mtext><mi>lo</mi></msup></mrow></math> of dedifferentiated in the disease course. In development, epithelial cell differentiation is induced by stromal signaling and cell contact. One of the stromal factors specific to prostate encodes proenkephalin (PENK). PENK can down-regulate scTF and up-regulate B2M in stem-like small cell carcinoma LuCaP 145.1 cells indicative of exit from the stem state and differentiation. In fact, prostate cancer cells can be made to undergo dedifferentiation or reprogramming by scTF transfection and then to differentiate by PENK transfection. Therapies need to be designed for treating the different cancer cell types. Extracellular anterior gradient 2 (eAGR2) is an adenocarcinoma antigen associated with cancer differentiation that can be targeted by antibodies to lyse tumor cells with immune system components. eAGR2 is specific to cancer as normal cells express only the intracellular form (iAGR2). For AGR2-negative stem-like cancer cells, factors like PENK that can target scTF could be effective in differentiation therapy.