Reversion of the PTCH

mutation back to wild-type

Acquisition

of a mutation in Smoothened that prevents inhibitor activity

Inactivation of an

alternative receptor tyrosine kinase pathway, such as EGFR

Increased expression

of multidrug efflux pumps that enhance intracellular inhibitor concentration

Persistent

Gli activation drives uncontrolled proliferation in neural progenitors and

basal epidermal cells

Gli target genes are

only transiently activated due to partial negative feedback by GLI3 repressor,

limiting tissue overgrowth

Constitutive SMO

activation leads to developmental arrest due to accumulation of non-functional

Gli proteins

PTCH upregulation

compensates for SMO activation, preventing tumour formation

PTCH mutations cause

aberrant activation of p53-dependent apoptosis, paradoxically promoting

tumorigenesis through up-regulation of basal cell proliferation

Loss of PTCH reduces

Hedgehog signalling, causing basal cells to proliferate uncontrollably

PTCH loss-of-function

makes cells more sensitive to UV-induced DNA damage, which directly triggers

carcinoma formation through uncontrolled basal cell proliferation

Loss

of PTCH function removes inhibition of Smoothened, causing persistent Hedgehog

pathway activation and uncontrolled basal cell proliferation

B-cell regulatory

pathways that reduce antibody-mediated immunity within the tumour

microenvironment

Immune

checkpoint pathways that regulate the activation state of cytotoxic T cells

within the tumour microenvironment

Angiogenic pathways

that stimulate tumour blood vessel formation within the tumour microenvironment

Extracellular matrix

synthesis pathways that increase tumour structural integrity within the tumour

microenvironment

Direct induction of

DNA damage within tumour cells

Blocking

communication between tumour cells and stromal fibroblasts

Inhibition of

growth-factor signalling between tumour cells

Disruption

of an immune checkpoint interaction that normally suppresses cytotoxic T-cell

responses against tumour cells

A recessive loss-of-function

mutation that disables both alleles of a proto-oncogene

Gene amplification

leading to increased transcription of an inactive signalling protein

A

dominant gain-of-function mutation that activates a proto-oncogene and promotes

oncogenic signalling

Deletion of a tumour

suppressor gene that normally inhibits cell proliferation

Uncontrolled

expansion of granule cell precursor populations normally located in the

external granular layer

Increased

differentiation of supportive Bergmann glial cells that guide neuronal

migration

Overproduction of

Purkinje neurons that regulate cerebellar signalling

Accelerated migration

of granule cells into the internal granular layer

A

somatic event that removes the remaining functional allele of a tumour

suppressor gene

A mutation that

inactivates both alleles of a tumour suppressor gene

Amplification of a

growth-promoting oncogene leading to increased signalling activity

A germline mutation

that activates a proto-oncogene

Loss

of E-cadherin that normally maintains epithelial tissue architecture

Up-regulation of

telomerase that extends telomeres and prevents cellular senescence

Increased expression

of VEGF that stimulates new blood vessel formation

Activation of

Cytochrome C involved in apoptosis signalling

The HER2 receptor is

expressed exclusively in tumour cells and therefore bypasses normal regulatory

mechanisms

The HER2 receptor cannot

participate in receptor dimerisation and signals through an alternative pathway

The HER2 receptor lacks the ability to bind extracellular ligand but readily forms

signalling-competent dimers with other HER family receptors

The HER2 receptor lacks

intrinsic tyrosine kinase activity and therefore depends on other receptors for

phosphorylation