Tumor Heterogeneity

tumors are not just made up of cancer cells

"normal" cells incorporated into a tumor (immune cells, fibroblasts, fat-adipocytes)

how we know tumors are monoclonal

-X chromosome inactivation -theoretically a tumor made of different cell types should have different origins -BUT because all the tumor cells have the same de-activated chromosome, the cells are all coming from one parent cell

consequences of tumor heterogeneity

-difficulty characterizing cancer (identifying mutations, epigenetic factors) -treatments of cancers is based on classification of the tumor usually from a biopsy (only looking at a small portion of tumor, marker may only be displayed in a fraction-reason some therapies have thresholds) -personalized medicine is based on defining the specific genetic insults in a patient's tumor, yet there may not be one specific set of insults (driver vs. passenger mutations)

cancer stem cells

-don't know where they come from or if they're real -likely tumors dependent (some cancers rely on rare progenitor populations, others have a predominant tumor generating population) -may come from normal stem or progenitor cells -may also come from cells that have de-differentiated and gained the ability for self-renewal

cancer evolution

-implies the process of natural selection on a cellular level -multiple stages of cancer represent its evolution and the multiple hits that must occur to the genome

Tumor heterogeneity is caused by:

All of the above (Clonal expansion of cancer cell mutants, Different differentiated phenotypes of cancer cells, Macrophage infiltrate)

Sequencing of a primary and metastatic tumor identified a mutation that was only found in the metastatic tumor. Which of these is not a possible explanation for this mutation?

Initial driver mutation of the cancer

According to the cancer stem cell hypothesis, treatment of cancer fails because

Therapies target differentiated cells

transformation to cancer

a multi-stage process

dysplasia

abnormal growth (cells without normal structure or phenotype)

basis of cancer

acquisition of genetic insults

monoclonal tumors

arise from one parent cell but are heterogenous

clonal amplification leads to tumor heterogeneity

certain mutations with greater competitive advantage mutate/proliferate more -tumor becomes made of many cancer cell types that all came from same original cell *different pressures can be applied following metastasis to get different mutations

stroma/micro-environment

collection of "normal" cells within and surrounding the tumor

metaplasia

different growth (cells of one type found somewhere else), look normal but not in right place

tumor clonality and evolution

each genetic insult could produce a proliferative advantage, so this cell type will outcompete other cells -permissive state of cancer allows for continuous mutation

hyperplasia

excessive growth

passenger mutation

genetic insult that does not provide any advantage but is allowed or maintained because of the damage permissive state of the cell

driver mutation/gene

genetic insult that provides an advantage to the tumor and causes the disease to progress

-plasia

growth

opposing ideas of tumoriogenesis

monoclonal vs polyclonal

challenges of passenger mutations

often ride along with the driver mutations, have no competitive advantage but maintained because of driver mutations

stem cell treatment relapse

target differentiated cells and leave the cancer stem cells to eventually cause relapse after the acquisition of additional insults that leave therapy ineffective

alternative treatment relapse

therapy resistant cells are always present in heterogeneous tumors and therapy just selects for those cells

cancer stem cell model

within a tumor, only certain populations of the cells have the capacity for unlimited self-renewal; these cells also have the ability to differentiate into multiple lineages