One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype

The phosphatidylinositol 3-Kinase AKT pathway in human cancer.

Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences

Proliferation, cell cycle and apoptosis in cancer

http://dipbsf.uninsubria.it/monti/BFPN%202009/mTOR.pdf

Defining the Role of mTOR in Cancer

There are ample genetic and laboratory studies that suggest the PI3K-Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K-Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.

/pdf/targeting-pi3k-signalling-in-cancer-opportunities-challenges-22a9u88icu.pdf

Targeting PI3K signalling in cancer: opportunities, challenges and limitations.

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

Pten/Mmac1+/− heterozygous mice exhibited neoplasms in multiple organs including the endometrium, liver, prostate, gastrointestinal tract, thyroid, and thymus. Loss of the wild-type allele was detected in neoplasms of the thymus and liver. Surprisingly, tumors of the gastrointestinal epithelium developed in association with gut lymphoid tissue. Tumors of the endometrium, thyroid, prostate, and liver were not associated with lymphoid tissue and appeared to be highly mitotic. In addition, these mice have nonneoplastic hyperplasia of lymph nodes that was caused by an inherited defect in apoptosis detected in B cells and macrophages. Examination of peripheral lymphoid tissue including lymphoid aggregates associated with polyps revealed that the normal organization of B and T cells was disrupted in heterozygous animals. Taken together, these data suggest that PTEN is a regulator of apoptosis and proliferation that behaves as a “landscaper” tumor suppressor in the gut and a “gatekeeper” tumor suppressor in other organs.

https://www.pnas.org/content/pnas/96/4/1563.full.pdf

Giorgio Catoretti

Papers

Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems