The cellular origins of cancer with particular reference to the gastrointestinal tract

Abstract

Summary Stem cells or their closely related committed progenitor cells are the likely founder cells of most neoplasms. In the continually renewing and hierarchically organized epithelia of the oesophagus, stomach and intestine, homeostatic stem cells are located at the beginning of the cell flux, in the basal layer of the oesophagus, the isthmic region of gastric oxyntic glands and at the bottom of gastric pyloric‐antral glands and colonic crypts. The introduction of mutant oncogenes such as KrasG12D or loss of Tp53 or Apc to specific cell types expressing the likes of Lgr5 and Mist1 can be readily accomplished in genetically engineered mouse models to initiate tumorigenesis. Other origins of cancer are discussed including ‘reserve’ stem cells that may be activated by damage or through disruption of morphogen gradients along the crypt axis. In the liver and pancreas, with little cell turnover and no obvious stem cell markers, the importance of regenerative hyperplasia associated with chronic inflammation to tumour initiation is vividly apparent, though inflammatory conditions in the renewing populations are also permissive for tumour induction. In the liver, hepatocytes, biliary epithelial cells and hepatic progenitor cells are embryologically related, and all can give rise to hepatocellular carcinoma and cholangiocarcinoma. In the exocrine pancreas, both acinar and ductal cells can give rise to pancreatic ductal adenocarcinoma (PDAC), although the preceding preneoplastic states are quite different: acinar‐ductal metaplasia gives rise to pancreatic intraepithelial neoplasia culminating in PDAC, while ducts give rise to PDAC via. mucinous cell metaplasia that may have a polyclonal origin.

EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas

“… 23 The cancer cell of origin in PDAC remains controversial; however, in vivo mouse studies indicate that tumorigenesis can develop from cells of exocrine acinar, ducts, and endocrine lineages. 24 , 25 Unlike rapidly proliferating epithelia such as intestine or skin, the adult pancreas is not actively renewing, has limited proliferative capacity during homeostasis, and relies on cell plasticity to regenerate in response to injury. 26 What is less understood is how the adult pancreas maintains tissue health following mutational insult.…”

Acinar Cell Carcinoma of Gastric Ectopic Pancreas Origin: A Case Report and Literature Review

“…In the second hypothesis, the tumor is thought to originate from pluripotent stem cells with different directions of differentiation. 11 However, most researchers currently favor the third hypothesis, which proposes that the tumor originates from the ectopic pancreas. The stomach and pancreas are both derived from the caudal or distal part of the embryonic foregut, and the abnormal differentiation of their inherent stem cells may be the origin of ectopic pancreases.…”

Aging and biliary tract cancers: Epidemiology, molecular biology, and clinical practice

“…[15][16][17][18] DDC-induced injury makes the oncogenically primed hepatocytes be reprogrammed to a cholangiocyte phenotype. 19,20 Both iCCA and extrahepatic cholangiocarcinoma exhibit higher incidence in non-Hispanic Asian/Pacific Islander populations than non-Hispanic White people. 12 It is emerging that in BTC, disease incidence and mortality are higher in patients with age of 80 or older than young population with age of less than 50.…”

“…Likewise, experimental iCCA can be also derived from hepatocytes, particularly under the influence of Notch overexpression 15–18 . DDC‐induced injury makes the oncogenically primed hepatocytes be reprogrammed to a cholangiocyte phenotype 19,20 . Both iCCA and extrahepatic cholangiocarcinoma exhibit higher incidence in non‐Hispanic Asian/Pacific Islander populations than non‐Hispanic White people 12 .…”