Samuel Asfaha

Samuel Asfaha
The University of Western Ontario | UWO · Department of Medicine

MD, PhD

About

130
Publications
8,055
Reads
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5,414
Citations
Citations since 2017
37 Research Items
2733 Citations
20172018201920202021202220230100200300400500
20172018201920202021202220230100200300400500
20172018201920202021202220230100200300400500
20172018201920202021202220230100200300400500
Additional affiliations
October 2014 - present
The University of Western Ontario
Position
  • Professor (Assistant)
February 2012 - August 2014
Columbia University
Position
  • Instructor
November 2008 - January 2012
Columbia University
Position
  • PostDoc Position

Publications

Publications (130)
Article
Background & aims: Colorectal cancer (CRC) is a leading cause of cancer death with a major risk factor being chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to CRC is not well understood. Methods: To investigate whether different forms of inflammation pose the same risk of cancer, we c...
Article
Full-text available
Background Colorectal cancer is the second leading cause of cancer death in Canada. A major risk factor for the development of colorectal cancer is chronic inflammation leading to colitis-associated cancer (CAC). We previously described a CAC mouse mode in which tumors arise from DCLK1+ tuft cells following loss of the tumor suppressor adenomatous...
Article
Full-text available
Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by remitting and relapsing symptoms of abdominal pain, diarrhea, nausea, fatigue, and poor sleep. Most patients with IBD require chronic immunosuppressive therapy to maintain their disease in remission. Due to their disease chr...
Article
Background and aims Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CA...
Article
Background Colorectal cancer (CRC) is the third leading cause of cancer death, with a major risk factor being chronic inflammation. Thus, patients with inflammatory bowel disease (IBD) are at an increased risk of CRC. Despite the clear association between inflammation and cancer, the mechanism by which colitis leads to CRC is still not well underst...
Conference Paper
Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment and play a critical part in cancer progression. However, the precise origin of the tumor stroma remains unknown, making it challenging to effectively target the cancer mesenchyme. Here, employing 4 different genetic fate mapping mouse models and a bone marrow...
Article
Background Colorectal cancer is the 2nd leading cause of cancer death in Canada. In rapidly dividing tissues such as the intestine or colon, only long-lived, multipotent, self-renewing tissue stem cells have longevity to accumulate mutations and serve as the cellular origin of cancer. In the small intestine, genetic fate mapping studies have demons...
Article
Background Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Canada. A major risk factor for this disease is chronic inflammation. Despite the clear link between inflammation and cancer, the exact mechanism by which colitis leads to cancer is unknown. Our group has previously shown that a rare cell type in the gut marked by the ex...
Article
Background Colorectal cancer (CRC) is the second leading cause of cancer death, with a major risk factor being chronic inflammation. Despite the clear association between inflammation and cancer, the mechanism by which colitis leads to CRC is not well understood. We recently showed that the presence of inflammation does not always correlate with co...
Article
Background Colorectal cancer (CRC) is the second leading cause of cancer death in Canada, with the major risk factor being chronic inflammation. As such, patients with inflammatory bowel disease (IBD) are at an increased risk of CRC. Despite the clear association between inflammation and cancer, the mechanism by which colitis leads to CRC is still...
Article
Background Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Canada. Inflammatory bowel disease (IBD), a chronic state of colonic inflammation, is a major risk factor for CRC. Despite the clear link between inflammation and cancer, the mechanism by which colitis leads to cancer is unknown. Doublecortin-like kinase-1 (Dclk1) is a m...
Article
During homeostasis, the colonic epithelium is replenished every 3–5 days by rapidly cycling Lgr5⁺ stem cells. However, various insults can lead to depletion of Lgr5⁺ stem cells, and colonic epithelium can be regenerated from Lgr5-negative cells. While studies in the small intestine have addressed the lineage identity of the Lgr5-negative regenerati...
Article
Full-text available
We used allogeneic bone marrow transplantation (BMT) and a mouse multistage cutaneous carcinogenesis model to probe recruitment of bone marrow-derived epithelial cells (BMDECs) in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with 12-O-tetradecanolyphorbol-13-acetate (TPA). BMDECs clustered in the lesiona...
Article
Background & aims: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelia...
Article
Background Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). This risk is related to disease extent, duration and severity. Current guidelines recommend routine colonoscopy 8–10 years after the initial onset of disease. However, no large controlled trials have investigated the efficacy of su...
Article
Background Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Canada. A major risk factor for this disease is chronic inflammation. For this reason, patients with inflammatory bowel disease (IBD), such as Crohn’s disease or Ulcerative colitis, require frequent colon cancer screening. Despite the clear link between inflammation and...
Article
Background Colorectal cancer (CRC) is the second leading cause of cancer death in Canada, with the major risk factor being chronic inflammation. How inflammation leads to cancer is not well understood. Our recent work has focused on a colonic epithelial cell known as the tuft cell that uniquely expresses the protein doublecortin-like kinase 1 (Dclk...
Article
Full-text available
Background Melena is a hallmark symptom of upper gastrointestinal bleeding and results from the digestion of blood lost proximal to the ligament of Treitz in the majority of cases. However, whether melena also predicts bleeding in the proximal small intestine (SI) in the setting of obscure gastrointestinal bleeding (OGIB) is unknown. Aims The obje...
Article
Background The intestinal and colonic epithelia are rapidly renewed every 3 to 5 days. In the intestine, at least two principal stem cell pools, comprised of rapidly cycling crypt based columnar (CBC) Lgr5⁺ cells and slower cycling Bmi1-expressing cells located above the crypt base, have been described. In the colon, however, we have recently ident...
Article
Full-text available
Mist1 was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also expressMist1. The relevance ofMist1expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Usi...
Article
Full-text available
Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here we describe an auto-/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc...
Article
Full-text available
Background and study aims Adenoma detection rate (ADR) is an important measure of colonoscopy quality, as are polyp, advanced ADR, and adenocarcinoma detection rates. We investigated whether performance report cards improved these outcome measures. Patients and methods Endoscopists were given report cards comparing their detection rates to the i...
Article
While controversy over the existence of adult pancreatic stem cells persists, it is now appreciated that the acinar compartment of the pancreas harbors heterogeneous progenitors. Recent single-cell analysis also demonstrated the presence of molecularly distinct, albeit morphologically identical, acinar cell sub-lineages. Previously, using lineage-t...
Article
Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1⁺ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium...
Article
Full-text available
WNT/β-catenin signalling is crucial for intestinal homoeostasis. The intestinal epithelium and stroma are the major source of WNT ligands but their origin and role in intestinal stem cell (ISC) and epithelial repair remains unknown. Macrophages are a major constituent of the intestinal stroma. Here, we analyse the role of macrophage-derived WNT in...
Article
All developing and adult organs are supported by connective tissues. We recently demonstrated that Gremlin 1 expressing cells in the bone (osteochondroreticular stem cells) and the bowel (intestinal reticular stem cells) are connective tissue stem cells, during development and healing. The contribution of these stem cells to the desmoplasia surroun...
Article
Intestinal crypts are maintained by long-lived intestinal stem cells (ISCs) which reside near the base of glands. Above the ISC pool, there are short-lived progenitors that can supply lineage-specific differentiated cell types into the villus. Notch and Wnt pathways play a key role for determining the stem/progenitor cell function and their cell fa...
Article
The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quies...
Article
Full-text available
CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) expand in the spleen during cancer and promote progression through suppression of cytotoxic T cells. An anti-inflammatory reflex arc involving the vagus nerve and memory T cells is necessary for resolution of acute inflammation. Failure of this neural circuit could promote procarcinogenic inflamm...
Article
The intestinal epithelium is renewed every 3-5 days from at least two principal stem cell pools. Actively cycling crypt based columnar (CBC) Lgr5(+) cells and slower cycling Bmi1-expressing or Krt19-expressing cells maintain the small intestinal and colonic epithelium in homeostasis and injury. Following acute epithelial damage, Lgr5+ stem cells ar...
Article
The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E...
Article
There are two major stem cell populations in the intestinal crypt region that express either Bmi1 or Lgr5; however, it has been shown that other populations in the crypt can regain stemness. In this study, we demonstrate that the transcription factor Nkx2.2 is expressed in enteroendocrine cells located in the villus and crypt of the intestinal epit...
Article
Background/Aims: There is increasing evidence that chronic sympathetic nervous system activation can lead to increased noradrenaline levels in the tumor microenvironment. This process has been associated with proliferative signals largely mediated by beta-adrenergic signaling. However, the mechanisms by which adrenergic neurotransmitters are delive...
Article
Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5(+) cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identific...
Article
The nervous system regulates epithelial homeostasis and tumorigenesis. However, the precise mechanism of tumor-associated neurogenesis in gut is still poorly understood. Here, we show that nerve growth factor (NGF), a member of the neurotrophin family, is markedly upregulated in the tumor microenvironment and plays a key role in tumor-associated ne...
Article
The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expre...
Article
ABSTRACT: The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here...
Article
Gastrin is a hormone that binds to the CCK2 receptor and promotes proximal gastric cancer, but inhibits distal gastric cancer development. However, the precise roles of the CCK2 receptor, and its alternative ligand, progastrin, in gastric carcinogenesis have not been clarified. In this study, we found that progastrin accelerated antral proliferatio...
Article
Introduction: In the rapidly proliferating gastrointestinal epithelium, long-lived tissue stem cells, characterized by multipotentiality and self-renewing ability, remain the most likely cellular origin for cancer. Previous studies have suggested actively cycling Lgr5+ stem cells are one cellular origin for intestinal adenomas. However, it has also...
Article
Full-text available
Objective Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interc...
Article
Introduction: Despite recent progress in the detection and management of pancreatic cancer it remains and almost uniformly lethal disease. Pancreatic ductal adenocarcinoma (PDAC) currently ranks as the fourth leading cause of cancer-related death in the U.S. and has the highest case mortality rate of all major cancers. While genetically engineered...
Article
Full-text available
Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker that has been proposed to identify quiescent and tumor growth-sustaining stem cells. DCLK1+ tuft cells are increased in inflammation-induced carcinogenesis; however, the role of these cells within the gastrointestinal epithelium and their potential as cancer-initiatin...
Article
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: The cellular origin and contribution of mesenchymal stem cells (MSCs) in the gastrointestinal tract, bone marrow and tumor microenvironment are unknown. More specific markers of MSCs are needed. We hypothesized that Grem1 expression would be a specific marker...
Article
Tumors are postulated to arise from tissue stem or progenitor cells. In the stomach, keratin 19 (K19) is thought to mark a potential progenitor cell within the gastric isthmus. To examine the contribution of tissue stem cells to the origin of gastric cancer, we generated a new K19-BAC-CreER transgenic line to study the lineage of K19+ cells and det...
Article
& Aims: Progastrin stimulates colonic mucosal proliferation and carcinogenesis through the cholecystokinin 2 receptor (CCKBR)-partly by increasing numbers of colonic progenitor cells. However, little is known about the mechanisms by which progastrin stimulates colonic cell proliferation. We investigated the role of bone morphogenetic proteins (BMPs...
Article
Background & aims: Interleukin (IL)-8 has an important role in initiating inflammation in humans, attracting immune cells such as neutrophils through their receptors CXCR1 and CXCR2. IL-8 has been proposed to contribute to chronic inflammation and cancer. However, mice do not have the IL-8 gene, so human cancer cell lines and xenograft studies hav...
Article
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: The clonal origin of tumors is not well understood. Previous studies using chimeric mice have suggested that the origin of tumors in the mammalian small intestine may be polyclonal, with 2 or more progenitor cells contributing to intestinal adenomas. In the...
Article
The gastrointestinal tract is supported by myofibroblasts (MF) that regulate epithelial homeostasis. In cancer the physiological stroma is replaced by activated cells including bone marrow (BM)-derived cancer-associated fibroblasts (CAFs) that drive carcinogenesis. MFs and a significant proportion of CAFs express αSMA. The origin of these cells and...
Article
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the US. Despite major efforts pancreatic cancer has the highest mortality rate of all major cancers with a 5-year survival rate below 5% while the survival rate f...
Article
Although a stem cell origin for tumors was postulated nearly 200 years ago, a critical role of keratin-15 expressing hair follicle stem cells in skin tumorigenesis has only recently been established. In addition to tissue stem cells, bone marrow cells can play a reparative function in damaged organs and contribute to cancer development as recently...
Article
Full-text available
Objective: Stromal cell-derived factor-1 (SDF-1/CXCL12), the main ligand for CXCR4, is overexpressed in human cancer. This study addressed the precise contribution of SDF-1 to gastric carcinogenesis. Design: SDF-1 transgenic mice were created and a Helicobacter-induced gastric cancer model was used in combination with H/K-ATPase-IL-1β mice. Gastri...
Article
Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely re...
Article
Introduction: Tissue stem cells, characterized by multipotentiality and self renewing ability, are not readily distinguishable from other resident cells. Tissue stem cells are believed to be present in small numbers that may remain quiescent, or divide frequently as previously shown with Lgr-5+ cells. In the gastric antrum, intestine and colon, epi...
Data
FAD spectral calibration, and corrected spectra of in-vitro pure fluorophore samples. Shows raw excitation spectra for three emission bands (red, green and blue) acquired on a sample of pure FAD (a 400 µM solution in phosphate buffered saline (PBS), Sigma Aldrich F6625). The excitation wavelength-dependent envelope (given by K in equations 1 and 2)...
Data
Axial stack of the small intestine beginning at the outer muscularis mucosa. Imaging the small intestine through the muscularis mucosa allows better visualization of the crypts in the lamina propria. This stack was acquired at 740 nm with a field of view of 375 µm on each side and a total depth of 170 µm. Note that at z = −115 µm, the villi begin t...
Data
False color merges of component images. In (A), component images are shown with false color with the merge at right. The color scheme used is consistent for all the unmixed images in B–F, with yellow corresponding to epithelium, white to lamina propria, blue to collagen, and green to lymphocytes. Scale bars for all images are 50 µm. (B) At the cryp...