Therapeutic implications of colon CSCs

Therapeutic implications of colon cancer stem cells by Eros Fabrizi and 3 co-authors, including Lucia Ricci-Vitiani, World J Gastroenterol 2010(Aug 21); 16(31): 3871-7. OA review. [FriendFeed entry][PubMed citation]. Abstract:

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.

Two publications about colorectal cancer

The Key to Stopping Colon Cancer? Med Tech Sentinel, August 30, 2009. Excerpt:

Scientists in Switzerland may have found a way to inhibit the growth of colon cancer in humans, says a new study published in EMBO Molecular Medicine. Researchers in Geneva discovered that by blocking a particular biological pathway, they could prevent the growth of tumors, metastatic lesions, and cancer stem cells. The Hedgehog-GL1 (HH-GL1) pathway appears to be crucial in the progression of colon cancer to an incurable, late stage. Cells use HH-GL1 to communicate with each other to determine position, growth and survival.

See also: 'Hedgehog' pathway may hold key to anti-cancer therapy, EurekAlert, August 26, 2009.

These news reports are about the publication: Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion by Frédéric Varnat and 6 co-authors, including Ariel Ruiz i Altaba, EMBO Molecular Medicine 2009(Aug 27) [Epub ahead of print][Abstract][Full text].

Another excerpt from The Key to Stopping Colon Cancer? (Med Tech Sentinel, August 30, 2009):

Earlier this month, scientists in North Carolina found another genetic target that may be useful in treating colorectal cancer. The pseudokinase ERBB3 is closely related to epidermal growth factor receptor (EGFR), which is already a target of several drugs used to treat colorectal cancer. Scientists found that genetically blocking ERBB3 was effective at preventing the disease in mice with colon cancer. In human colon cancer cells, removing ERBB3 caused a dramatic increase in cell death.

About the publication: Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium by Daekee Lee and 8 co-authors, including David W Threadgill, J Clin Invest 2009(Aug 17) [Epub ahead of print][PubMed Citation][Full text].

Microtubule-associated kinase DCAMKL-1 a novel target for anti-CSC-based strategies?

Scientists discover stem cell protein linked to cancer growth, Kerentech, May 23, 2009. Excerpt:

Researchers have studied stem cell proteins for years, but Houchen and Anant said they not only found a new cancer protein, but discovered how the protein works to turn off a natural tumor suppressor and turn on a cancer-causing gene.

The results of their research will be published in an upcoming issue of the journal Gastroenterology.

See also: Scientists Discover How Cancer Protein Works, News release, OU Cancer Institute. Excerpt:

The latest work involves a new stem cell protein. Houchen and Anant discovered that this protein was responsible for regulating a natural tumor suppressor. It is the first such evidence of a stem cell protein regulating a tumor suppressor. When the protein, which is found in cancer, was increased, it caused the tumor suppressor to go down and the tumor grew in research models. When the protein was reduced or "knocked down," the level of tumor suppressor went up and the tumor stopped growing. Scientists also found that when they stopped the protein, the expression of a cancer-causing gene also went down.

The relevant publication is: Selective Blockade of DCAMKL-1 Results in Tumor Growth Arrest by a Let-7a MicroRNA-Dependent Mechanism by Sripathi M Sureban and 6 co-authors, including Shrikant Anant and Courtney W Houchen, Gastroenterology 2009(May 12) [PubMed Citation].

Another related publication from this group: Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice by Randal May and 5 co-authors, Stem Cells 2008(Mar); 26(3): 630-7 [Epub 2007 Nov 29]. [PubMed Citation][Full text is publicly accessible (via Gratis OA)].

Distinguishing colorectal precancer from cancer

Reversibility of Aberrant Global DNA and Estrogen Receptor-alpha Gene Methylation Distinguishes Colorectal Precancer from Cancer by Rulong Shen and 5 co-authors, including Jian-Xin Gao, Int J Clin Exp Pathol 2009; 2(1): 21-33 [Epub 2008 Apr 20][PMC version]. PubMed Abstract:

Alterations in the global methylation of DNA and in specific regulatory genes are two epigenetic alterations found in cancer. However, the significance of epigenetic changes for diagnosis and/or prognosis of colorectal cancer have not been established, although it has been extensively investigated. Recently we have identified a new type of cancer cell called precancerous stem cells (pCSCs) and proposed that cancer may arise from a lengthy development process of tumor initiating cells (TICs) --> pCSCs --> cancer stem cells (CSCs) --> cancer, which is in parallel to histological changes of hyperplasia (TICs) --> precancer (pCSCs) --> carcinoma (CSCs/cancer cells), accompanied by clonal evolutionary epigenetic and genetic alterations. In this study, we investigated whether aberrant DNA methylation can be used as a biomarker for the differentiation between premalignant and malignant lesions in the colorectum. The profile of global DNA and estrogen receptor (ER)-alpha gene methylation during cancer development was determined by analysis of 5-methylcytosine (5-MeC) using immunohistochemical (IHC) staining, dot blot analysis or a quantitative gene methylation assay (QGMA). Herein we show that global DNA hypomethylation and ER-alpha gene hypermethylation are progressively enhanced from hyperplastic polyps (HPs) --> adenomatous polyps (APs) --> adenomatous carcinoma (AdCa). The aberrant methylation can be completely reversed in APs, but not in AdCa by a nonsteroidal anti-inflammatory drug (NSAID) celecoxib, which is a selective inhibitor of cyclooxygenase-2 (Cox-2), suggesting that the epigenetic alterations between colorectal precancer (AP) and cancer (AdCa) are fundamentally different in response to anti-cancer therapy. In normal colorectal mucosa, while global DNA methylation was not affected by aging, ER-alpha gene methylation was significantly increased with aging. However, this increase did not reach the level observed in colorectal APs. Taken together, reversibility of aberrant global DNA and ER-alpha gene methylation distinguishes colorectal precancer from cancer.

[This article is publicly accessible].