Dr. Weeks’ Comment: Throwing rocks at the hornet’s (think “cancer TUMOR cells”) will result in the hornets (think “cancer STEM cells) flying out enraged and stinging you in self-defense. What we are learning over and over again in cancer research which you the cancer patients are not being told by your oncologists is that killing tumor cells just makes the really lethal cancer STEM cells more numerous and more virulent.
“…Importantly, we observed that standard drug treatment is indeed effective in vivo in delaying tumor outgrowth but after cessation of treatment tumor growth is accelerated.This is consistent with the hypothesis that CSC when left unharmed will rapidly regenerate the original tumor…”
Ask your oncologist about what her or his proposed treatment will do to your cancer stem cells. Your life depends upon the answer.
Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4
Journal: Cell STEM CELL
Authors: Matilde Todaro, Mileidys Perez Alea, et al
SUMMARY
A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell markerCD133 that accounts around 2% of the cells inhuman colon cancer. The CD133+cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immune deficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133+cells. Further analysis revealed that the CD133+cells produce and utilizeIL-4 to protect themselves from apoptosis. Consistently, treatment with IL-4Raantagonistor anti-IL-4 neutralizing antibody strongly enhances the antitumor efficacy of standard chemotherapeutic drugs through selective sensitization of CD133+cells. Our data suggest that colon tumor growth is dictated by stem-like cells that are treatment resistant due to the autocrine production of IL-4.
Discussion
Cancers are heterogeneous populations of cells at multiple differentiation stages that could be the result of acquired mutations and epigenetic differences. Alternatively, differential expression of differentiation markers could be due to aberrant differentiation orchestrated by a stem cell population (Phillips et al., 2006). Although both hypotheses are difficult to proof, our current data show that colon cancer lesions consist of a large fraction of differentiated cancer cells and a small population of cells that express CD133 stem cell marker. From 10 of the 21 tumors studied, spheroid cultures could be derived, and this appears more effective when studying MSI and high-grade tumors. Although this is not a 100% correlation, it suggests that MSI colon carcinomas may contain specific mutations that facilitate their in vitro growth. In contrast to the sphere cultures, the adherent cell populations established from the same tumor were not tumorigenic in mice, while they display epithelial features and reflect the histological variants from which they were initially derived. Similar observations were also made for colon (Ricci-Vitiani et al., 2007) and other solid tumors, such as brain, melanoma, ovarian, prostate, and breast carcinoma (Bapat et al., 2005; Collins et al., 2005; Dontuet al., 2004; Fang et al., 2005; Singh et al., 2004).In analogy with stem cells, CSC are suggested to resist death-inducing signals as they are slow cycling and ex-press high levels of drug transporters (Dean et al., 2005).CSC were also suggested to express high levels of antiapoptotic proteins and thus resist apoptotic stimuli (Eramoet al., 2006). Our spheroid cultures confirm these ideas and show that stem-like tumor cells effectively resist oxaliplatin, 5-FU, and TRAIL-induced death cell. Chemotherapy resistance may in part be due to the slow cycling of CSC, but TRAIL sensitivity is not dependent on the cell cycle. We therefore believe that expression of anti-apoptotic proteins dictate this resistance. In agreement, sensitization of spheroid cells with anti-IL-4 down regulates expression of three tested anti-apoptotic proteins: cFLIP, PED, and Bcl-xL. Considerable data suggest that some interleukins promote cancer cell survival and expansion by stimulating expression of anti-apoptotic genes. For example,IL-3 increases BclxLlevels in myeloid and pro-B cell (Kieslinger et al., 2000). Similarly, IL-10 upregulates Bcl-2 expression in germinal center B cells, while IL-4 increases survival of malignant B cells (Dancescu et al., 1992). Others and we recently demonstrated that carcinoma cells produce IL-4 and IL-10 and that this alters sensitivity to death receptor- and cytotoxic drug-induced cell death. Neutralization of both IL-4 and IL-10 significantly in-creased the effectiveness of death receptors and antineoplastic drugs on primary cancer cells (Stassi et al., 2003;Todaro et al., 2006). We now extend these observations to colon CSC both in vitro and in vivo. Our data indicate that IL-4-depended protection is essential for cell death resistance of colon CSC. Importantly, we observed that standard drug treatment is indeed effective in vivo in delaying tumor outgrowth but after cessation of treatment tumor growth is accelerated.This is consistent with the hypothesis that CSC when left unharmed will rapidly regenerate the original tumor.
Our findings on IL-4 (prove) to be a general phenomenon in colon cancer as it was observed in all samples tested (16 out 18 tested) and not related to stage, location of the tumor, or MSI. These findings may thus provide the means to counteract tumor regeneration by selectively killing CSC.
“… The contribution of IL-4 to chemotherapy resistance described in this work contribute to a better understand-ing of the biological consequences of IL-4 up regulation and the factors that may determine tumor escape from current therapies. Combined, our observations may (prove) to be of critical importance in future antitumor therapies, as it has been hypothesized that a surviving small population of cancer stem cells could be responsible for tumor reappearance after an apparent complete regression and thus could contribute to minimal residual dis-ease (MRD). The data presented here provide a rational to use anti-IL-4 as a novel approach in antitumor therapies and suggest further investigations into the under-lying mechanism of tumor-specific IL-4 expression and resistance.”