Metastasis progression
Mieloma multiplo
Linear Progression Cancer cells disseminate through the organism after acquiring metastatic features inside the primary cancer
Parallel progression Cancer cells leave the primary cancer before the acquirement of a Metastati competence. Acquire the metastatic phenotype during progression to the metastatic site a) Accumulation of mutations indipendently and parallel to the primary cancer b) During dissemination acquire the capability to growth in different microenvironment c) The maturation of the metastatic phenotype can occur at different times
Premetastatic niche
TGF-β: plays a crucial role in the process Lung Metastasis 4 TGF- β Bone Metastasi Smad signaling Angiopoietin-Like Protein Induces the expression of factors activationg the osteoclasts such as PTHrP, IL-1 Induces the expression of ANGPTL4 that increases the permeability of the lung vessels Activation of different pathways
METASTASIS Latent NO LATENT Metastasis develop after a long time from diagnosis Metastasis develop after a short time from diagnosis Different tumors colonize the same tissue with different kinetics : different time lapse between infiltration and colonization
The pre-malignant cells: Metastasis with NO latency: 1)Are already competent or 2)Acquire metastatic competence in the early phases of transformation: 3) <The metastatic competence is regulated by epigenetic mechanisms i.e.: Adenocarcinoma of pancreas and lung: the cells acquire very early the ability to infiltrate and metastatize.
Latent Metastasis : Different genetic background Different microenvironments Expression of genes encoding for survival Expression of genes suppressors of the metastasis DTCs They are quiscent cells: - They are blocked in G 0 or - Equilibrium between proliferation and apoptosis i.e. Breast cancer, prostate cancer and melanoma
DTCs can acquire metastatic competence Breast cancer cells Secretion of factors that Activate osteoclasts: PTHRP, IL-1, IL-6, TNF-α Expression and secretion of RANKL from osteoblasts RANKL induces the maturation of osteoclasts from the myeloid progenitors Degradation of the bone matrix
DTC (Disseminated Tumor Cells): cancer cells from the primary cancer and migration towards an ectopic compartment NON METASTATIC METASTATIC
How can we explain this observation? LINEAR PROGRESSION A strong similarity in the genotypesl between the primary cancer and the DTC in bone marrow and lymphonodes in the same patient. However, it is difficult to exclude that cells already metastatic can be present in the primary tumors and impossible to detect Parallele PROGRESSION The data support this model. Moreover, both in virus breast cancer in mouse (MMTV) and in some human cancers DTC in a stage pre-invasive of the cancers have been detected
In cancers of Breast, Prostate and Esophagous,the comparison between the cariograms in DTC and in cells of primary cancer from the same patients show: Less chromosomic rearrangements in DTC compared to the primary cancers Different allelic equilibrium in many microsatellites Differences in specific mutations in the same gene i.e. ERBB2 its amplification is the most frequent mutation in DTC and it is not the same as primary cancer indicating that the amplification occurred at different times
Cancer therapies
Breast cancer
HER forms heterodimers and signals through the RAS-AKT pathway
PHILADELPHIA CHROMOSOME CHRONIC LIMPHATIC LEUKEMIA ABL: TYROSIN KINASE
IMATINIB
Immune therapies
CAR cells
Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape.
The ease with which genes can be introduced into T cells enables the expression of multiple gene products to further shape the targeting and functional attributes of engineered T cells. T he molecules used in conjunction with CARs for the purpose of increasing T cell potency or safety include a range of synthetic receptors, including chimaeric co-stimulatory receptors,, Notchbased receptors, antigen-specific inhibitory receptors and others, and additional gene products designed to act in the tumour microenvironment or augment T cell safety. Thus, while secondgeneration CARs have already demonstrated and validated the enormous potential of synthetic T cell engineering, one may anticipate a number of further advances in T cell therapy based on multiplexed enhancements.
The successful TCR- and CAR-based therapies have to date made use of autologous T cells, which imposes individualized cell manufacturing and makes inter-patient variability unavoidable, even with selection of defined subsets. Immunosuppressive drugs may mitigate such complications, but are not an option because unimpeded anti-tumour function of the infused T cells is essential. The risk of exacerbating GVHD after introducing CARs in donor T cells is real, albeit variable137 140, depending in part on the CAR design An alternative to manipulating mature T cells is to generate CAR T cells in vitro from pluripotent stem cells. Stem cell reprogramming offers potential access to an unlimited source of therapeutic T lymphocytes and provides an excellent platform for performing additional engineering intended to enhance the therapeutic potential of induced T cells.
More signal is better
Channelling potassium to fight cancer
An evolutionary view
Tumours are subject to the same rules of natural selection as any other living thing. Clinicians are now putting that knowledge to use. Clinicians are now putting that knowledge to use. 166 NATURE VOL 532 14 APRIL 2016 Tesina. Tumor Evolution as a Therapeutic Target Nabil Amirouchene-Angelozzi, Charles Swanton and Alberto Bardelli DOI: 10.1158/2159-8290.CD-17-0343 Published August 2017
Research 29 November 2017 Nature Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth Giovanni Germano, Simona Lamba[ ]Alberto Bardelli Methyl-directed mismatch repair 5 MutS, MutL, ATP ADP+Pi 5 MutH, ATP ADP+Pi CH 3 CH 3 CH 3 CH MutS 3 MutL 1. Mismatch within 1 kb of methylated GATC 2. MutS and MutH bind to mismatched spots along the DNA (except C-C) 3. DNA on both sides of the Mitsmatch runs through MutS:MutL complex 5 3 5 3 CH 3 CH 3 MutS MutH MutH MutL CH 3 CH 3 4. MutH binds to MutL and to GATC 5. Endonuclease of MutH cleaves unmethylated DNA at hemimethylated GATC