Carcinogenesis, inverse

Morphogenesis and the

Precision Medicine, what the
surgeons need to know
Muhammad Farooq Afzal MD FCPS FRCS FACS MCPS(HPE)
Fellowship in Advanced Laparoscopic and Bariatric Surgery(USA)
Professor and HOD Surgery PGMI/AMC/LGH
President Society of Surgeons Lahore Chapter
Key Questions
• What is cancer and how cancer develops?
• What is the concept of morphogenesis and inverse morphogenesis?
• What is precision medicine?
• What is the role of precision medicine in the current management of
cancer patients?
 What is cancer?

Disregulated cell division due to genetic mutations

and epigenetic factors leading to Malignant
transformation
Normal DNA
Malignant transformation is evolutionary
• Normal
• Hyperplasia
• Metaplasia
• Dysplasia
• Neoplasia
• Metastasis
Six Hall Marks of Cancer (Hannah and Weinberg 2000
Hannah and
Weinberg 2011
Carcinogenesis in Colorectal Cancer
 Is there any relationship
between cancer and normal
morphengenesis ?
Normal Morphogenesis(Ontogenesis)
• Totipotent cells to Monopotent cells
• Dedifferentiation to differentiation
• Normal Morphogenesis is a process of folding of the Epigenome.
• Epithelial Mesenchymal Transition during embryogenesis leads to
major reprogramming of gene expression that leads to alterations in
cell fate and behaviour.
Normal Mammalian Morphogenesis
Normal Morphogentic fields
Last Five Stages of Ontogenetic Anatomy of Uterine
cervix(Hockel )
23 stages
Cancer: Process of inverse
Morphogenesis(catagenesis)
• Cancer cells, Cancer clones and Cancer stem cells
• CSCs are aggressive tumour cells that share characteristics of
embryonic progenitor cells
• Epigenomic unfolding
• Cancer Spreads in Respective Cancer fields before abutting to the next
stage in development

Hockel et al 2007
Tumor Microenvironment
Local spread of cancer
Cancer cells spread along the cancer fields
Ontogenetic Anatomy of Cervical Cancer

Hockel,2009
Proof of concept
What is Precision Medicine?
Each cancer has its own signature
TCGA and PANCANCER ANALYSIS
Breast Cancer ,an example of Precision
Medicine
The Birth of Targeted Therapies
From Genetic Mutations to Molecular targets
Immunotherapy(checkpoint inhibitors)
Precision Medicine in Advanced Colon Cancer
Molecular Subytypes Treatment of choice

MSI High(15%) Immunotherapy(checkpoint

inhibitors)
BRAF(10%) Bevicuzamab

HER2 (5%) Trastuzumab+TKI

Stage Four IV disease is no
more a death sentence
Molecular subtypes of cancer
 Summary
• Cancer is unregulated cellular proliferation due to genomic
instability producing different molecular subtypes
• Cancer cells exhibit reverse morphogenesis and EMT and
spreads along the cancer fields hence resection of the
respective cancer field is important to prevent local
recurrence
• Precision medicine is identifying these Molecular signatures
and then treating them with Targeted therapies
• Stage iv disease is no more a death sentence within 6
months