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12.1: Cancer in General - Biology


A cancer is an uncontrolled proliferation of cells. This distinguishes cancers — malignant tumors — from benign growths like moles where their cells eventually stop dividing (usually). Even more important, benign growths differ from malignant ones in not producing metastases; that is, they do not seed new growths elsewhere in the body.

Cancers are clones. No matter how many trillions of cells are present in the cancer, they are all descended from a single ancestral cell. Evidence: Although normal tissues of a woman are a mosaic of cells in which one X chromosome or the other has been inactivated, all her tumor cells — even if from multiple sites — have the same X chromosome inactivated.

Cancers begin as a primary tumor. Most (maybe all) solid tumors shed cells into the lymph and blood. Most of these lack the potential to develop into tumors. However, some of the shed cells are able to take up residence and establish secondary tumors — metastases — in other locations of the body. These metastases, not the primary tumor, are what usually kills the patient.

Cancer cells are usually less differentiated than the normal cells of the tissue where they arose. Many people feel that this reflects a process of dedifferentiation, but I doubt it. Rather, evidence is accumulating that cancers arise in precursor cells — stem cells or "progenitor cells" — of the tissue: cells that are dividing by mitosis producing daughter cells that are not yet fully differentiated.

A cancer is an uncontrolled proliferation of cells.

Cancer is a Genetic Disease

What probably happens is:

  • A single cell — perhaps an adult stem cell or progenitor cell — in a tissue suffers a mutation (red line) in a gene involved in the cell cycle, e.g., an oncogene or tumor suppressor gene.
  • This results in giving that cell a slight growth advantage over other dividing cells in the tissue.
  • As that cell develops into a clone, some if its descendants suffer another mutation (red line) in another cell-cycle gene.
  • This further deregulates the cell cycle of that cell and its descendants.
  • As the rate of mitosis in that clone increases, the chances of further DNA damage increases.
  • Eventually, so many mutations have occurred that the growth of that clone becomes completely unregulated.
  • The result: full-blown cancer. (Genetic analysis reveals an average of 63 mutations in pancreatic cancers; almost as many in one type of adult brain cancer, but only 11 somatic mutations in a case of brain cancer in a child.)
  • Sequencing samples from several areas in a primary tumor, as well as from some of its metastases, reveals a different collection of mutations from sample to sample. This finding is reinforced by the sequencing of the genome of individual cells from a single tumor each of which shows a unique pattern of shared and unique mutations. (The ability to sequence the genome of a single cell reveals that even normal cells in an adult have accumulated a suite of somatic mutations that differs from cell to cell. However, the rate of somatic mutations in these normal cells is only a fourth of that in cancer cells.)

So even though all the malignant cells in a cancer are descended from a single original cell — and thus are members of a single clone — they are no longer genetically-identical. As the tumor develops, its various cells develop a variety of additional mutations, and these give rise to "subclones" of varying degrees of malignancy with varying

  • propensity to metastasize;
  • susceptibility to treatment by anticancer drugs;
  • propensity to relapse after apparently-successful therapy.

These findings should stimulate a reexamination of the use of chemotherapy.

  • While chemotherapy may wipe out dominant subclones in a tumor, there is evidence that is also exerts a selective pressure for the expansion of more malignant, previously-minor, subclones.
  • Most chemotherapeutic agents damage DNA so while killing off some cells, they will raise the mutation rate in any surviving cells perhaps encouraging the outgrowth of even more malignant subclones.

Evidence: In a group of patients with chronic lymphocytic leukemia, those receiving chemotherapy survived for shorter periods than those that did not.

Cancer Stem Cells

Stem cells are cells that divide by mitosis to form either two stem cells, thus increasing the size of the stem cell "pool", or one daughter that goes on to differentiate, and one daughter that retains its stem-cell properties. There is growing evidence that most of the cells in leukemias, breast, brain, skin, ovarian, and colon cancers are not able to proliferate out-of-control (and to metastasize). Only those members of the clone that retain their stem-cell-like properties (~2.5% of the cells in a tumor of the colon) can do so.

There is a certain logic to this. Most terminally-differentiated cells have limited potential to divide by mitosis and, seldom passing through S phase of the cell cycle, are limited in their ability to accumulate the new mutations that predispose to becoming cancerous. Furthermore, they often have short life spans — being eliminated by apoptosis (e.g., lymphocytes) or being shed from the tissue (e.g., epithelial cells of the colon). The adult stem cell pool, in contrast, is long-lived, and its members have many opportunities to acquire new mutations as they produce differentiating daughters as well as daughters that maintain the stem cell pool.

Colon cancer

  • Begins with the development of polyps in the epithelium of the colon. Polyps are benign growths.
  • As time passes, the polyps may get bigger.
  • At some point, nests of malignant cells may appear within the polyps
  • If the polyp is not removed, some of these malignant cells will escape from the primary tumor and metastasize throughout the body.

Examination of the cells at the earliest, polyp, stage, reveals that they contain one or two mutations associated with cancer. Frequently these include

  • the deletion of a healthy copy of the APC (adenomatous polyposis coli) gene on chromosome 5 leaving behind a mutant copy of this tumor suppressor gene

    Two results:

    1. One of the functions of the APC gene product is to destroy the transcription factor β-catenin thus preventing it from turning on genes that cause the cell to divide. With no, or a defective, APC protein, the normal brakes on cell division are lifted.
    2. Another function of the APC protein is to help attach the microtubules of the mitotic spindle to the kinetochores of the chromosomes. With no, or a defective, APC product available, chromosomes are lost from the spindle producing aneuploid progeny.
  • a mutant oncogene (often RAS).
  • deletion and/or mutation of the tumor suppressor gene p53

The graph also explains why cancer has become such a common cause of death during the twentieth century. It probably has very little to do with exposure to the chemicals of modern living and everything to do with the increased longevity that has been such a remarkable feature of the 20th century. A population whose members increasingly survive accidents and infectious disease is a population increasingly condemned to death from such "organic" diseases as cancer.

Causes of Cancer

Cancers are caused by

  • anything that damages DNA; that is anything that is mutagenic
    • radiation that can penetrate to the nucleus and interact with DNA
    • chemicals that can penetrate to the nucleus and damage DNA. Chemicals that cause cancer are called carcinogens.
  • anything that stimulates the rate of mitosis. This is because a cell is most susceptible to mutations when it is replicating its DNA during the S phase of the cell cycle.
    • certain hormones (e.g., hormones that stimulate mitosis in tissues like the breast and the prostate gland)
    • chronic tissue injury (which increases mitosis in the stem cells needed to repair the damage)
    • agents that cause inflammation (which generates DNA-damaging oxidizing agents in the cell)
    • certain other chemicals; some the products of technology
    • certain viruses
    (Considering that from conception to death, an estimated 1016 mitotic cell divisions occur in humans, it is remarkable that cancer is not more common than it is.)

Viruses and Cancer

Many viruses have been studied that reliably cause cancer when laboratory animals are infected with them. What about humans? The evidence obviously is indirect but some likely culprits are:

  • two papilloma viruses that can cause cancer of the cervix and other regions of the genitals (male as well as female).
  • the hepatitis B and hepatitis C viruses, which infect the liver and are closely associated with liver cancer (probably because of the chronic inflammation they produce)
  • some herpes viruses such as the Epstein-Barr virus (implicated in Burkitt's lymphoma) and KSHV that is associated with Kaposi's sarcoma (a malignancy frequently seen in the late stages of AIDS)
  • two human T-cell lymphotropic viruses, HTLV-1 and HTLV-2

But note that the viral infection only contributes to the development of cancer.

  • Many people are infected by these viruses and do not develop cancer.
  • When cancers do arise in infected people, they still follow our rule of clonality. Many cells have been infected, but only one (usually) develops into a tumor.

So again it appears that only if an infected cell is unlucky enough to suffer several other types of damage will it develop into a tumor.Nevertheless, widespread vaccination against these viruses should not only prevent disease but lower the incidence of the cancers associated with them. A vaccine against hepatitis B is available as are two vaccines (Gardasil® and Cervarix®) against the most dangerous papilloma viruses.

Are Cancers Contagious?

The short answer is NO.

The reason: Cancer cells, like all cells in the body, express histocompatibility molecules on their surface. So like any organ or tissue transplant between two people (other than identical twins), they are allografts and are recognized and destroyed by the recipient's immune system.

However, there are some exceptions.

  1. Although tumors are not transmissible, viruses are. So any of the viruses described in the previous section can be spread from person to person and predispose them to the relevant cancers.
  2. There have been a number of cases where, unbeknownst to the surgeon, an organ (e.g., a kidney) from a donor with melanoma has allowed the growth of the same melanoma in the recipient. Transplant recipients must have their immune system suppressed if the transplant is not to be rejected, but their immunosuppression also prevents their immune system from attacking the melanoma cells. Stopping immune suppression cures the recipient (but also causes loss of the kidney).
  3. Canine transmissible venereal tumor (CTVT). This tumor spreads from dog to dog during copulation. Although the MHC alleles on the tumor cells are only weakly expressed, they do eventually cause the tumor to be rejected.
  4. Devil facial tumor disease (DFTD). The carnivorous Tasmanian devil is a marsupial living in Tasmania, Australia. The population is threatened by a facial cancer that is spread through bites. The population is highly inbred, thus closely-related genetically, and the MHC alleles on the tumor are only weakly expressed. So it may be these factors that allow the tumor to grow unchecked.
  5. The soft-shell clam, Mya arenaria, along the North Atlantic coast of North America is being devastated by a leukemia that spreads from animal to animal perhaps as these filter feeders ingest sea water in which leukemic cells have been shed. These mollusks are invertebrates and lack powerful tissue rejection molecules like the MHC of vertebrates.
  6. There are extremely rare cases where a pregnant woman with cancer (a leukemia or melanoma) has transmitted the cancer across the placenta to her fetus (whose immune system has yet to develop).

The Hallmarks of Cancer

In the year 2000 Douglas Hanahan and Robert Weinberg published a paper — The Hallmarks of Cancer — outlining 6 characteristics that are acquired as a cell progresses toward becoming a full-blown cancer. In the 4 March 2011 issue of Cell, they add 4 other features.

  1. Uncontrolled proliferation.
  2. Evasion of growth suppressors. Among the many mutations found in cancers, one or more inactivate tumor suppressor genes.
  3. Resistance to apoptosis (programmed cell death).
  4. Develop replicative immortality; i.e., avoid the normal process of cell senescence.
  5. Induce angiogenesis; that is, promote the development of a blood supply.
  6. Invasion and metastasis — the ability of tumor cells to invade underlying tissue and then to be carried to other parts of the body where secondary tumors develop (metastasis). During this process, the normal adhesion of cells to each other and to the underlying extracellular matrix (ECM) are disrupted.
  7. Genomic instability. Cancer cells develop chromosomal aberrations and many (hundreds) of mutations. Most of the latter are "passenger" mutations, but as many as 10 may be "drivers" of the cancerous transformation.
  8. Inflammation. Tumors are invaded by cells of the immune system, which promote inflammation. One effect of inflammation is the production of reactive oxygen species (ROS). These damage DNA and other molecules.
  9. Changed energy metabolism. Even if well-supplied with oxygen, cancer cells get most of their ATP from glycolysis not cellular respiration.
  10. Evade the immune system.

Cancer stem cells and cancer therapy

Cancer stem cells (CSCs) are a subpopulation of tumour cells that possess the stem cell properties of self-renewal and differentiation. Stem cells might be the target cells responsible for malignant transformation, and tumour formation may be a disorder of stem cell self-renewal pathway. Epigenetic alterations and mutations of genes involved in signal transmissions may promote the formation of CSCs. These cells have been identified in many solid tumours including breast, brain, lung, prostate, testis, ovary, colon, skin, liver, and also in acute myeloid leukaemia. The CSC theory clarifies not only the issue of tumour initiation, development, metastasis and relapse, but also the ineffectiveness of conventional cancer therapies. Treatments directed against the bulk of the cancer cells may produce striking responses but they are unlikely to result in long-term remissions if the rare CSCs are not targeted. In this review, we consider the properties of CSCs and possible strategies for controlling the viability and tumourigenecity of these cells, including therapeutic models for selective elimination of CSCs and induction of their proper differentiation.


Department of Cancer Biology

Over 80% prostate cancer deaths are involved with bone metastases. Second-line hormonal therapies such as enzalutamide improve overall patient survival only by several months in about 50% of the patients, and almost all patients develop drug resistance. There is an urgent need to determine the mechanisms of drug resistance and to develop new approaches for overcoming such resistance and for better treatment of prostate cancer bone metastasis. This study is currently supported by an R01 (2019-2024) from NCI.

2. Influence of bone microenvironment on tumor dormancy and reactivation

It has been proposed that the early disseminated tumor cells are the cells of origin for cancer recurrence. Up to 70% of prostate cancer patients have disseminated tumor cells in the bone marrow at the time of initial diagnosis. These cells remain dormant initially but proliferate later to overt metastases that eventually kill patients. Understanding the mechanisms of dormancy and reactivation will provide novel avenues for metastases prevention and inhibition.

3. Drivers of bone-specific metastasis

Divers for bone-specific metastasis and subsequent bone destruction are still largely unknown. Applying bed to bench side approach. We collaborate with Bin Chen’s (MSU) team analyzing big data of patient and virtual drug screening to instruct our basic research in determining the drivers and testing the efficacy of targeting at pre-clinical setting.

4. Intermittent fasting effects on bone metastasis and drug resistance

In recent years, intermittent fasting has been shown many health benefits that are not simply the result of weight loss. Many clinical trials of intermittent fasting in cancer patients are currently in progress. However, no conclusive benefits in cancer incidence, metastasis, treatment responses or drug resistance are reached. Using our unique preclinical mouse models, we aim to answer these questions and further determine the mechanisms of the actions at molecular and cellular level.

R01 CA230744-01A1, National Cancer Institute
Li, Xiaohong (PI)
04/19/19-03/31/24
Influence of bone microenvironment on drug resistance in prostate cancer bone metastasis
Role: PI

Completed Research Support

W81XWH-16-1-0136, Department of Defense
Ganguly (PI)
06/01/16-05/31/18
Notch Signaling in Prostate Cancer Cells Promotes Osteoblastic Metastasis
Role: Mentor

W81XWH-12-1-0271, Department of Defense
Li, Xiaohong (PI)
07/15/12-08/31/16
Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development
Role: PI

53010UPL2, Van Andel Institute Faculty Innovation Award
Li, Xiaohong (PI)
12/16/17-11/30/20
Developing tools to keep prostate cancer cells dormant in the bone microenvironment
Role: PI

53010PL2, Van Andel Institute Employee Impact Fund
Li, Xiaohong (PI)
05/05/15-11/30/20
Sensitizing chemo-resistant cancer stem cells in non-small cell lung cancers
Role: PI

53010A, Van Andel Institute Start-up
Li, Xiaohong (PI)
09/01/12-11/30/16
TGFbeta signaling in cancer bone metastases
Role: PI


Normal Cell Division: Growth & Replacement

Virchow was correct when he concluded that cells arise from others cells, i.e., new cells are born through the division of one cell into two through the process of mitosis. The need for new cells continues throughout our lives, but it is greatest in early life. A fertilized egg divides into two cells, which give rise to four, and those give rise to eight, and then to 16, and 32, and 64, and so on. In a fully grown adult, of course, the rate of cell proliferation is much less, and under normal circumstances, cell division in an adult takes place only when signals indicate the need to replace cells that have been lost, damaged, or worn out.


Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells

Melanoma is a highly aggressive malignant tumor with an exceptional ability to develop resistance and no curative therapy is available for patients with distant metastatic disease. The inhibitor of apoptosis protein (IAP) family has been related to therapy resistance in cancer. We examined the importance of the IAPs in the resistance to the commonly used chemotherapeutic agent dacarbazine (DTIC) and the apoptosis inducer TRAIL (TNF-related apoptosis inducing ligand) in malignant melanoma. The data presented show that the expression of IAPs is universal, concomitant and generally high in melanoma cell lines and in patient samples. Depleting IAP expression by siRNA tended to reduce cell viability, with XIAP reduction being the most efficient in all four cell lines examined (FEMX-1, LOX, SKMEL-28 and WM115). The combined treatment of XIAP siRNA and DTIC showed a weak improvement in two of four cell lines, while all four cell lines showed enhanced sensitivity towards TRAIL (AdhCMV-TRAIL) after XIAP depletion. In addition, cIAP-1, cIAP-2 and survivin down-regulation sensitized to TRAIL treatment in several of the cell lines. Cells exposed to TRAIL and XIAP siRNA showed increased DNA-fragmentation and cleavage of Bid, procaspase-8, -9, -7 and -3 and PARP, and change in the balance between pro- and anti-apoptotic proteins, indicating an enhanced level of apoptosis. Furthermore, the combined treatment reduced the ability of melanoma cells to engraft and form tumors in mice, actualizing the combination for future therapy of malignant melanoma.


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ProbatioN

A semester GPA below 3.0 or an incomplete grade (I) will result in the student being placed on academic probation. If a semester GPA of 3.0 is not attained or the Incomplete grade is not cleared during the subsequent semester of full- time enrollment, the student may be dismissed from the program or allowed to continue for 1 additional semester based on advisor appeal to the Graduate School.

ADVISOR / COMMITTEE

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CREDITS PER TERM ALLOWED

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A candidate for a doctoral degree who fails to take the final oral examination and deposit the dissertation within five years after passing the preliminary examination may be required to take another preliminary examination and to be admitted to candidacy a second time.

Doctoral degree students who have been absent for ten or more consecutive years lose all credits that they have earned before their absence. Individual programs may count the coursework students completed prior to their absence for meeting program requirements that coursework may not count toward Graduate School credit requirements.

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These resources may be helpful in addressing your concerns:

Grievance Policy for Graduate Programs in the School of Medicine and Public Health

Any student in a School of Medicine and Public Health graduate program who feels that they have been treated unfairly in regards to educational decisions and/or outcomes or issues specific to the graduate program, including academic standing, progress to degree, professional activities, appropriate advising, and a program’s community standards by a faculty member, staff member, postdoc, or student has the right to complain about the treatment and to receive a prompt hearing of the grievance following these grievance procedures. Any student who discusses, inquiries about, or participates in the grievance procedure may do so openly and shall not be subject to intimidation, discipline, or retaliation because of such activity. Each program’s grievance advisor is listed on the “Research” tab of the SMPH intranet.

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The School of Medicine and Public Health Office of Basic Research, Biotechnology and Graduate Studies requires that each graduate program designate a grievance advisor, who should be a tenured faculty member, and will request the name of the grievance advisor annually. The program director will serve as the alternate grievance advisor in the event that the grievance advisor is named in the grievance. The program must notify students of the grievance advisor, including posting the grievance advisor’s name on the program’s Guide page and handbook.

The grievance advisor or program director may be approached for possible grievances of all types. They will spearhead the grievance response process described below for issues specific to the graduate program, including but not limited to academic standing, progress to degree, professional activities, appropriate advising, and a program’s community standards. They will ensure students are advised on reporting procedures for other types of possible grievances and are supported throughout the reporting process. Resources on identifying and reporting other issues have been compiled by the Graduate School.

  1. The student is advised to initiate a written record containing dates, times, persons, and description of activities, and to update this record while completing the procedures described below.
  2. If the student is comfortable doing so, efforts should be made to resolve complaints informally between individuals before pursuing a formal grievance.
  3. Should a satisfactory resolution not be achieved, the student should contact the program’s grievance advisor or program director to discuss the complaint. The student may approach the grievance advisor or program director alone or with a UW-Madison faculty or staff member. The grievance advisor or program director should keep a record of contacts with regards to possible grievances. The first attempt is to help the student informally address the complaint prior to pursuing a formal grievance. The student is also encouraged to talk with their faculty advisor regarding concerns or difficulties.
  4. If the issue is not resolved to the student’s satisfaction, the student may submit a formal grievance to the grievance advisor or program director in writing, within 60 calendar days from the date the grievant first became aware of, or should have become aware of with the exercise of reasonable diligence, the cause of the grievance. To the fullest extent possible, a grievance shall contain a clear and concise statement of the grievance and indicate the issue(s) involved, the relief sought, the date(s) the incident or violation took place, and any specific policy involved.
  5. On receipt of a written grievance, the following steps will occur. The final step must be completed within 30 business days from the date the grievance was received. The program must store documentation of the grievance for seven years. Significant grievances that set a precedent may be stored indefinitely.
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    4. The faculty committee will make a decision regarding the grievance. The committee’s review shall be fair, impartial, and timely. The grievance advisor or program director will report on the action taken by the committee in writing to both the student and the person toward whom the grievance was directed.
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    5. The SMPH Office of Basic Research, Biotechnology, and Graduate Studies must store documentation of the grievance for seven years. Grievances that set a precedent may be stored indefinitely.

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    Other


    Best Oncology and Cancer Biology colleges in the U.S. 2021

    Georgetown University offers 3 Oncology and Cancer Biology degree programs. It's a large, private not-for-profit, four-year university in a large city. In 2019, 14 Oncology and Cancer Biology students graduated with students earning 8 Master's degrees, and 6 Doctoral degrees.

    Wake Forest University offers 1 Oncology and Cancer Biology degree programs. It's a medium sized, private not-for-profit, four-year university in a midsize city. In 2019, 3 Oncology and Cancer Biology students graduated with students earning 3 Doctoral degrees.

    University of Wisconsin-Madison offers 2 Oncology and Cancer Biology degree programs. It's a very large, public, four-year university in a large city. In 2019, 3 Oncology and Cancer Biology students graduated with students earning 3 Doctoral degrees.

    University of Michigan-Ann Arbor offers 2 Oncology and Cancer Biology degree programs. It's a very large, public, four-year university in a midsize city. In 2019, 3 Oncology and Cancer Biology students graduated with students earning 2 Doctoral degrees, and 1 Master's degree.

    University of Chicago offers 2 Oncology and Cancer Biology degree programs. It's a large, private not-for-profit, four-year university in a large city. In 2019, 7 Oncology and Cancer Biology students graduated with students earning 4 Doctoral degrees, and 3 Master's degrees.

    Stanford University offers 1 Oncology and Cancer Biology degree programs. It's a large, private not-for-profit, four-year university in a large suburb. In 2019, 5 Oncology and Cancer Biology students graduated with students earning 5 Doctoral degrees.

    University of Colorado Denver/Anschutz Medical Campus offers 1 Oncology and Cancer Biology degree programs. It's a very large, public, four-year university in a large city. In 2019, 6 Oncology and Cancer Biology students graduated with students earning 6 Doctoral degrees.

    University of Miami offers 2 Oncology and Cancer Biology degree programs. It's a large, private not-for-profit, four-year university in a small city. In 2019, 7 Oncology and Cancer Biology students graduated with students earning 6 Doctoral degrees, and 1 Master's degree.

    Vanderbilt University offers 2 Oncology and Cancer Biology degree programs. It's a large, private not-for-profit, four-year university in a large city. In 2019, 5 Oncology and Cancer Biology students graduated with students earning 5 Doctoral degrees.

    University of Southern California offers 1 Oncology and Cancer Biology degree programs. It's a very large, private not-for-profit, four-year university in a large city. In 2019, 3 Oncology and Cancer Biology students graduated with students earning 3 Doctoral degrees.


    12.1: Cancer in General - Biology

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    Contents

    Cancer systems biology finds its roots in a number of events and realizations in biomedical research, as well as in technological advances. Historically cancer was identified, understood, and treated as a monolithic disease. It was seen as a “foreign” component that grew as a homogenous mass, and was to be best treated by excision. Besides the continued impact of surgical intervention, this simplistic view of cancer has drastically evolved. In parallel with the exploits of molecular biology, cancer research focused on the identification of critical oncogenes or tumor suppressor genes in the etiology of cancer. These breakthroughs revolutionized our understanding of molecular events driving cancer progression. Targeted therapy may be considered the current pinnacle of advances spawned by such insights.

    Despite these advances, many unresolved challenges remain, including the dearth of new treatment avenues for many cancer types, or the unexplained treatment failures and inevitable relapse in cancer types where targeted treatment exists. [11] Such mismatch between clinical results and the massive amounts of data acquired by omics technology highlights the existence of basic gaps in our knowledge of cancer fundamentals. Cancer Systems Biology is steadily improving our ability to organize information on cancer, in order to fill these gaps. Key developments include:

    • The generation of comprehensive molecular datasets (genome, transcriptome, epigenomics, proteome, metabolome, etc.) data collection [12]
    • Computational algorithms to extract drivers of cancer progression from existing datasets [13]
    • Statistical and mechanistic modeling of signaling networks [14]
    • Quantitative modeling of cancer evolutionary processes [6]
    • Mathematical modeling of cancer cell population growth [15]
    • Mathematical modeling of cellular responses to therapeutic intervention [16]
    • Mathematical modeling of cancer metabolism [10]

    The practice of Cancer Systems Biology requires close physical integration between scientists with diverse backgrounds. Critical large-scale efforts are also underway to train a new workforce fluent in both the languages of biology and applied mathematics. At the translational level, Cancer Systems Biology should engender precision medicine application to cancer treatment.

    High-throughput technologies enable comprehensive genomic analyses of mutations, rearrangements, copy number variations, and methylation at the cellular and tissue levels, as well as robust analysis of RNA and microRNA expression data, protein levels and metabolite levels. [17] [18] [19] [20] [21] [22]

    List of High-Throughput Technologies and the Data they generated, with representative databases and publications

    Technology Experimental data Representative database
    DNA-seq, NGS DNA sequences, exome sequences, genomes, genes TCGA, [23] GenBank, [24] DDBJ, [25] Ensembl [26]
    Microarray, RNA-seq Gene expression levels, microRNA levels, transcripts GEO, [27] Expression Atlas [28]
    MS, iTRAQ Protein concentration, phosphorylations GPMdb, [29] PRIDE, [30] Human Protein Atlas [31]
    C-MS, GC-MS, NMR Metabolite levels HMDB [32]
    ChIP-chip, ChIP-seq Protein-DNA interactions, transcript factor binding sites GEO, [27] TRANSFAC, [33] JASPAR, [34] ENCODE [35]
    CLIP-seq, PAR-CLIP, iCLIP MicroRNA-mRNA regulations StarBase, [36] miRTarBase [37]
    Y2H, AP/MS, MaMTH, maPPIT Protein-protein interactions HPRD, [38] BioGRID [39]
    Protein microarray Kinase–substrate interactions TCGA, [23] PhosphoPOINT [40]
    SGA, E-MAP, RNAi Genetic interactions HPRD, [41] BioGRID [42]
    SNP genotyping array GWAS loci, eQTL, aberrant SNPs GWAS Catalog, [43] dbGAP, [44] dbSNP [45]
    LUMIER, data integration Signaling pathways, metabolic pathways, molecular signatures TCGA, [23] KEGG, [46] Reactome [47]

    The computational approaches used in cancer systems biology include new mathematical and computational algorithms that reflect the dynamic interplay between experimental biology and the quantitative sciences. [48] A cancer systems biology approach can be applied at different levels, from an individual cell to a tissue, a patient with a primary tumour and possible metastases, or to any combination of these situations. This approach can integrate the molecular characteristics of tumours at different levels (DNA, RNA, protein, epigenetic, imaging) [49] and different intervals (seconds versus days) with multidisciplinary analysis. [50] One of the major challenges to its success, besides the challenge posed by the heterogeneity of cancer per se, resides in acquiring high-quality data that describe clinical characteristics, pathology, treatment, and outcomes and integrating the data into robust predictive models [51] [19] [20] [21] [22] [52] [53]

    Mathematical modeling can provide useful context for the rational design, validation and prioritization of novel cancer drug targets and their combinations. Network-based modeling and multi-scale modeling have begun to show promise in facilitating the process of effective cancer drug discovery. Using a systems network modeling approach, Schoerberl et al. [54] identified a previously unknown, complementary and potentially superior mechanism of inhibiting the ErbB receptor signaling network. ErbB3 was found to be the most sensitive node, leading to Akt activation Akt regulates many biological processes, such as proliferation, apoptosis and growth, which are all relevant to tumor progression. [55] This target driven modelling has paved way for first of its kind clinical trials. Bekkal et al. presented a nonlinear model of the dynamics of a cell population divided into proliferative and quiescent compartments. The proliferative phase represents the complete cell cycle (G (1)-S-G (2)-M) of a population committed to divide at its end. The asymptotic behavior of solutions of the nonlinear model is analysed in two cases, exhibiting tissue homeostasis or tumor exponential growth. The model is simulated and its analytic predictions are confirmed numerically. [56] Furthermore, advances in hardware and software have enabled the realization of clinically feasible, quantitative multimodality imaging of tissue pathophysiology. Earlier efforts relating to multimodality imaging of cancer have focused on the integration of anatomical and functional characteristics, such as PET-CT and single-photon emission CT (SPECT-CT), whereas more-recent advances and applications have involved the integration of multiple quantitative, functional measurements (for example, multiple PET tracers, varied MRI contrast mechanisms, and PET-MRI), thereby providing a more-comprehensive characterization of the tumour phenotype. The enormous amount of complementary quantitative data generated by such studies is beginning to offer unique insights into opportunities to optimize care for individual patients. Although important technical optimization and improved biological interpretation of multimodality imaging findings are needed, this approach can already be applied informatively in clinical trials of cancer therapeutics using existing tools. [57]

    • Cancer Genomics
    • Statistical and mechanistic modelling of cancer progression and development
    • Clinical response models / Modelling cellular response to therapeutic interventions
    • Sub-typing in Cancer.
    • Systems Oncology - Clinical application of Cancer Systems Biology

    In 2004, the US National Cancer Institute launched a program effort on Integrative Cancer Systems Biology [58] to establish Centers for Cancer Systems Biology that focus on the analysis of cancer as a complex biological system. The integration of experimental biology with mathematical modeling will result in new insights in the biology and new approaches to the management of cancer. The program brings clinical and basic cancer researchers together with researchers from mathematics, physics, engineering, information technology, imaging sciences, and computer science to work on unraveling fundamental questions in the biology of cancer. [59]


    Master of Science in Cancer Biology

    The MS program in Cancer Biology offers a strong didactic and laboratory curriculum in cancer biology with a major focus on molecular oncology. Our goal is to provide intensive research training for students who are interested in a career in academia, medicine, industry, or related careers in which first-hand research experience is an asset. Research interests in the Department of Oncology are diverse and dynamic, allowing students to choose from a broad spectrum of topics for their research thesis. Students are encouraged to attend weekly departmental seminars, Grand Rounds presentations and annual symposia. These regular interactions between students and faculty help our students develop oral communication and collaboration skills for future success.

    Degree Requirements

    The master's degree in Cancer Biology is offered under Plan A only. A minimum of 30 credits, eight of which must be from thesis research, and the completion of an original research project are required to receive a MS degree. The coursework includes 12 credits of compulsory courses and 10 credits of elective courses (listed below). A minimum GPA of 3.0 must be maintained throughout the MS program. Students should select an advisor and committee as early as possible in the second semester of year 1 to begin full time thesis research. Students should strive to publish one peer-reviewed paper as first or second author to demonstrate the quality of their research.

    Plan A Curriculum (Total 30 cr)

    Required courses (12 cr):

    MGG 7010 Molecular Biology & Genetics (4 cr)
    BMB 7010 General Biochemistry (4 cr)
    CB 7210 Fundamentals of Cancer Biology (3 cr)
    CB 7800 Ethics (1 cr)

    Elective courses (10 cr):

    CB 7220 Molecular Biology of Cancer Development (3 cr)
    CB 7240 Cancer chemotherapy (2 cr)
    CB 7300 Special Topics (1-4 topics, 1 cr each)
    CB 7410 Cancer Immunology and Immunotherapy Cr. 3 (Every other winter)
    CB 7430 Cancer epidemiology (2 cr)
    CB 7460 Mechanism of neoplasia: Cell signaling (3 cr)
    CB 7600 Applied Cancer Biostatistics (2 cr)
    BMS 7115 Technology Commercialization (1 cr)
    MGG 7030 Functional Genomics and Systems Biology Cr. 2 (Winter)

    CB 8999 Master's thesis research (8 cr)

    Admission Requirements

    Admission to the MS program is contingent upon admission to the Graduate School and the graduate programs of the School of Medicine. Qualified applicants must have a BS or BA degree from an accredited college or university, preferably with a major in biology, chemistry, physics, or a closely related discipline. A complete application includes the basic application form, personal statement, official transcripts from previous institutions, and three letters of reference. International students must be proficient in English as determined by satisfactory performance on the Test of English as a Foreign Language (TOEFL) examination. TOEFL scores should be reported to Wayne State University using institution code 1898. Applications must be submitted online by March 1 st . Graduate School Admissions policies can be found at the Office of Graduate Admissions.

    Contact Information

    Administrative Office for MS Program in Cancer Biology
    Department of Oncology
    Wayne State University School of Medicine
    421 E Canfield Street
    Detroit, MI 48201


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