Biomed Neoplasm

Fundamental Hallmarks of Cancer

- Sustaining Proliferative Signalling

- Evading growth supressors

- activating invasion and metastasis

- enabling replicative immortality

- inducing angiogenesis

- resisting cell death

Most Frequent mutated oncogene in pancreatic ductal ademocarcinoma (PDAC)

K-Ras arises from the cells lining the pancreatic ducts, activation (frequency mutation >90%)

Difference between a benign and malignant neoplasm

invasion of surrounding tissues

Properties of Neoplasm

slow growth rate, growth stimulus is cell intrinsic, resemblance to tissue of origin, non-invasive

cancer most common in Australia in 2012 according to AIHW

breast cancer

cancer most lethal in Aus 2021

lung cancer

key event leading to death of most cancer patients

Metastasis

what is pre-metastatic niche

promotes establishment of metastasised tumour cells in other organ. location in body by creating right microenvironment. Ensures that when tumour cells reach destination they have

• supportive stromal cells

• growth factors

• reduced immune surveillance

• a matrix structure that facilities attachment and proliferation

AA most abundant in plasma in cancer cell catabolic processes

Glutamine

Glutaminolysis - cells convert glutamine into TCA cycle metabolites (provide intermediastes for AA and drive energy aquisition)

upregulated in cancer cells

The Gleasons System of tumour grading is applied to describe which cancer

Prostate Cancer

two most common patterns of growth seen in the biopsy sample are each given a number from 1-5, then these two numbers are added together to give the Gleason score

Goes from well differentiated —> poorly differentiated (Anaplastic)

what imaging technique takes advantage of the tendency of cancer cells to use Warburg effect to obtain energy

FDG-PET

uses radioactive tracer to visualise how tissues and organs function in relation to glucose metabolism

A patient with breast cancer has a 4 cm tumour, with cancer cells identified in 7 lymph nodes in the armpit, and metastases present in the liver. What stage describes their cancer?

Stage IV

• only stage where cancer is found somewhere else is Stage IV

Category 1 = breast cancer found 1-3 lymph nodes in armpit

Category 2 = breast cancer found

• 4-9 lymph nodes in the armpit

• 1 or more lymph node under breast bone NOT any in lymph nodes in armpit

Category 3 = breast cancer found

• 10 or more lymph nodes in armpit

• 1 or more lymph nodes above or below collarbone

• 1 or more lymph nodes under breast bone AND 1 or more lymph nodes in armpit

  

A patient with breast cancer has an 8 cm tumour, with cancer cells identified in 9 lymph nodes in the armpit, and metastases present in several long bones. Which of the following stages describes their cancer (according to the breast cancer-specific staging system)?

Stage IV

What clinical activity is tumour markers most generally used for

Follow-Up

all tumour markers are useful for follow up

what are the activators for angiogenesis

-        VEGF-A

-        VEGF-B,-C

-        FGF1 (aFGF)

-        FGF2 (bFGF)

-        Other FGFs

what are the inhibitors of angiogenesis

-        Thrombospondin 1, 2

-        Interferon alpha/ beta

-        Angiostatin

-        Endostatin

-        Collagen IV fragments

How does p53, the ‘guardian of the genome’, protect against the accumulation of DNA damage in normal cells and contrast this to cancer cells in which p53 is mutated?

Normal Cells = Stalls cell cycle until DNA damage is repaired. Promotes DNA repair processes. If DNA damage cant be repaired, induces apoptosis

Cancer cells = without p53 activity, DNA is not repaired and cell cycle progresses, leading to the accumulation of multiple DNA lesions in a single cell lineage.

Name the two genes most frequently associated with hereditary breast cancer and the role they play in a normal cell.

BRAC1 and BRAC2, which play a role in homologous recombination/ repair of DNA damage

 

Contrast external beam radiation and brachytherapy.

External beam – linear accelerator focussed on tumour

Brachytherapy – locally placed nuclear isotopes that undergo radioactive decay

What do the terms T, N, M, X and O refer to in the TNM method of cancer staging?

T = size and extent of primary tumour

N = number of nearby lymph nodes that have cancer

M = whether cancer is metastised

X = cannot be measured

O = not present/ cannot be found

Name the two major histological subtypes of lung cancer and indicate which is the most common.

Small cell carcinoma

Non-small cell lung carcinoma (NSLC) (most common)

Which organs are the most common sites for metastases across all cancers?

Bone, Brain, Liver, Lungs

What is the most common type of cancer in Australia?

Non-melanoma skin cancer (aka keratinocyte cancers)

Name the two different types of graft used in haematopoietic stem cell transplantation and a specific or type of tumour that this technique is used to treat.

Autologous

Allogeneic

Myeloma/ Leukaemia/ Lymphoma

Describe one way in which you could make a mouse model of Pancreatic Cancer.

KPC mice

Patient-derived xenografts - take a tumour cell from patient and put it into an immunodeficient mice

-        Immunodeficient mice

-        Subcutaneous or orthotopic

match the terms

1.     Herceptin        a. Chemotherapy

2.     Given prior to primary treatment   b. Adjuvant therapy

3.     Topoisomerase inhibitor       c. Targeted therapy

4.     Given after primary treatment        d. Neoadjuvant therapy

 

Herceptin – targeted therapy

Given prior to treatment – neoadjuvant therapy

Topoisomerase inhibitor – chemotherapy

Given after primary treatment – adjuvant therapy

Examples of benign neoplasms

adenomas - glandular epithelial tissue

hemoangiomas - blood vessels

meningiomas - meninges

fibroids or fibromas - connective tissue

lipomas - adipose cells

hamartomas - mixture of tissue

oncogene

mutated proliferative gene (gene that has potential to cause cancer)

Proto-oncogene: normal cellular counterpart of an oncogene

function is activated in cancer cells

e.g., K-Ras, cSrc, cMyc

Tumour Suppressor

inhibitor of cellular growth

function is inactivated in cancer cells

both alleles need to be mutated/ deleted

e.g., p53, Rb

Cell Cycle Regulation

Ras and Myc proto-oncogenes infuse D and E type cyclins

these cyclins complex with cyclin-dependent kinases (CDKs) and promote S phase entry/ transition (checkpoint progression), after which cell-cycle progression is GF independent

Apoptosis

Caspase 8 - directly activates caspase 3, intrinsic pathway

caspase 3 = executioner

Dysregulation of Apoptosis (things that stop apoptosis)

hallmark of cancer

• impaired receptor signalling pathway

• disrupted balance of Bcl-2 family of proteins

• defects/ mutations in p53

• reduced expression of caspases

• increased expression of IAPs

additional hallmarks of cancer

avoiding immune destruction

tumour promoting inflammation

genome instability and mutation

deregulating cellular energetics

Genome instability in a cancer cell

Cancer cell —> DNA damage/ mutation —> damages repair mechanisms, inability to sense damage, inability to arrest —> damage —> damage to apoptotic pathway, mitosis —> perpetuation of error to daughter cells, rapid accumulation of genomic damage —> leads to accumulation of more key cancer cell characteristics

normal cell - mediated by p53 predominantly

DNA damage/ mutation —> arrest —> repair attempt —> 1. Extensive damage —> Apoptosis OR 2. correction —> mitosis

Autophagy

1. Vesicle nucleation

2. vesicle elongation

3. vesicle docking and fusion with lysosome

4. vesicle breakdown and content degradation

“self-eating”

important for maintenance

digested into precursor molecules e.g., proteins to AA’s

Cancer classification

defined by cell/ tissue type of origin

carcinoma - epithelial cells

sarcoma - connective tissues

melanoma - melanocytes

lymphoma - lymphocytes

leukaemia - bone marrow resident cells

myeloma - bone marrow resident lymphocytes

glioma - glial cells

2 categories of Lymphoma

1. hodgkin lymphona

2. non-hodgkin lymphona

Cachexia

weakness and wasting of the body due to severe chronic illness

tumour markers

hormone - e.g., human chorionic gonadotrophin (HCG) secreted by choriocarcinoma

enzymes - e.g., prostate-specific antigen in prostate carcinoma

tumour antigens - e.g., carcinoembryonic antigen (CEA) in colorectal carcinoma

useful for:

• screening

• monitoring treatment

• assessing follow up

• diagnosis

• prognosis

Screening for cancer

1. Test must detect the disease earlier than routine methods

2. Earlier treatment must lead to improved outcomes

3. Benefits of screening must be greater than the risks of any subsequent diagnostic and therapeutic treatment

Screening for breast cancer

self-examination

clinical examination/ mammography

genetic testing: BRAC1/2

Lung Cancer Staging

NSCLC

• Occult (hidden) stage - cancel cells found in sputum or other fluids from lung, but no cancer in other tests

• Stage O (carcinoma in situ) - cancer in top layers of cells lining the air passages (not spread to lymph nodes or distant areas of the body

• Stages I, II & III ( all have A and B parts) - involve cancer increasing in size and spreading to nearby lymph nodes

• Stage IV - cancer may have spread to opposite lung, space around lungs or heart or other organs, e.g., bone, liver and brain

small cell lung cancer

• limited stage - caner is only 1 side of chest (possibly incl. lymph nodes) and can be treated with a single radiation field

• extensive stage - cancer spread widely throughout the lung, to the other lung, to lymph nodes, on the other side of the chest or distant organs

imaging

non-invasive medical imaging at multiple times in the course of the illness for managemet

• detection

• characterising lesions

• locoregional and systemic staging

• prognosis

• assessing therapeutic responses

• precisely guiding biopsies and therapies

radiogrpagy, CT, ultrasonography

MRO and nuclear medicine methods, PET

Adjuvant therapy

additional treatment given after the primary treatment to lower the risk that the cancer will come back

neoadjuvant therapy

treatment given as a first step to shrink a tumour prior to the main treatment

targeted therapies

act on specific molecular targets

• often cytostatic (block tumour cell proliferation)

prostate cancer treatment

rely on testosterone to grow —> prostatectomy

external beam radiation and brachytherapy

BUT - the tumours themselves can produce their own testosterone

what is neoplasm

Abnormal mass of tissue that forms from dysfunctional cells (non cancerous)

Define Cancer

Diseases where abnormal cells divide without control and can invade nearby tissues (aka ‘malignant’ tumour)

screening for colon cancer

• colonoscopy: polyps; early cancer

• stool testing for blood/ DNA

• carcinoembryonic antigen (CEA) in blood

screening for prostate cancer

prostate specific antigen (PSA) in blood - activated by androgen receptor in prostate cells

benign enlargement and acute chronic inflammation leads to increased PSA levels