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Cancer Biology and Pathogenesis

why and how do we approach the study of cancer using comparative approaches?

Cancer is the leading cause of death in humans under the age of 85, as well as the leading cause of disease-related death in dogs. As such, it has gained exceptional importance in our society. Both genetic and environmental factors have major effects on the temporal occurrence of cancer, and there is thus a new emphasis to learn more about how these factors influence cellular and molecular changes in cancer. Dogs and people are susceptible to many of the same types of cancer and the natural history (incidence, age of onset, location, progression, outcome) of many cancer types is similar in both species. Our pet dogs share our environment closely, allowing us to examine not only the heritable risk factors, but also those associated with the environment. Moreover, when compared to humans, dogs have shorter generational life spans (as many as five or more related generations frequently co-exist), extended pedigrees with detailed family histories, and more homogeneous genetic backgrounds, which provide unique opportunities to address questions about the origin and behavior of cancer. The answers we obtain studying cancers of dogs will contribute to our ultimate goals to design strategies for prevention and treatment of cancer in both dogs and people.

To understand the implications of cancer, one must first realize that cancer is not a simple disease. Rather, the term cancer describes a large number of diseases whose only common feature is uncontrolled cell growth and proliferation. A very important concept that is now universally accepted is that “cancer is a genetic disease, although it is not always heritable.” Tumors arise from cells that accumulate mutations which eliminate normal constraints of proliferation and genetic integrity. These mutations provide cells a selective growth advantage within their environment. This is essentially the same evolutionary phenomenon that we call “natural selection”, albeit on a microscopic scale. Various theories have been proposed to explain the genetic basis of cancer. One explanation invokes stochastic (random) events – the inherent error rate of enzymes that control DNA replication during each division introduces about 1 in 1,000,000 to 1 in 10,000,000 mutations for each base that is replicated during each round of replication. The genome consists of many millions of base pairs, so each daughter cell is likely to carry at least a few mutations in its DNA. Most of these mutations are silent; that is, they do not present any problems to the cell’s ability to function. However, others can disable tumor suppressor genes or activate proto-oncogenes that respectively inhibit or promote cell division and survival. An alternative hypothesis is that mutations are not stochastic, but rather “directed” due to the presence of a “mutator phenotype,” where the factors that control DNA replication and repair are inherently prone to more errors than would be expected by simple stochastic events in particular individuals. This leads to different cancer predispositions, which would be higher than the mean in such individuals, and might explain why not all people (or dogs) exposed to similar environmental carcinogens develop the same forms cancer at the same rate. There is strong evidence to support both mechanisms (stochastic and directed) in people and animals.

Focus on Canine Cancer
For this program, we seek to define peculiar genetic traits that are the cause of cancer in dogs (and by extension, humans). Mutations of specific genes that increase the probability, or risk, that an individual (actually a cell) will develop a tumor. In most cases (estimated to be >95%), these mutations occur “sporadically”, that is, they alter the DNA of non-reproductive (somatic) cells. These mutations arise in susceptible individuals upon exposure to certain environmental insults, although the risk is not necessarily shared by relatives of the affected individual. Nevertheless, identifying the patterns of mutations associated with specific tumor types is likely to provide information to obtain a more accurate prognosis, and to develop more effective treatments.

On the other hand, in those rare cases where mutations occur in reproductive cells, they are passed on in the germ line. Identification of such mutations should help us predict relative cancer risk in individuals (or the likelihood of individuals to produce progeny with elevated cancer risks), allowing us to invest in practices to modify the environment that may reduce or eliminate the risk (cancer prevention). The investigation of cancer susceptibility in families or breeds of dogs is of critical importance to dog breeders and dog owners alike. Unlike other heritable conditions, genetic susceptibility to cancer may not manifest in disease until a dog has reached middle age, and long after it has achieved breeding potential. When present, this genetic susceptibility may be due to a process called loss of heterozygosity. Individuals inherit two copies of each gene upon conception, one from the sire, and one from the dam. Each of these gene copies is called an “allele.” A family or breed may have through the course of time, lost a functional allele of a “tumor suppressor gene” through mutation. The affected individuals are heterozygous (that is, they have two different alleles, and only one is functional). These individuals may not develop disease (cancer), unless the second, functional copy of the gene in question is mutated in a cell that retains the capacity to divide. Even in the best of circumstances, genetic analysis can only predict the probability or provide a relative risk, rather than a definitive assessment of whether or not the individual will in fact develop cancer.

Selected Results from Our Laboratory
NOTE: If you wish to obtain information for ongoing studies, eligibility criteria, informed consent forms, or instructions for participation, please go to the STUDY INFO area of the site. If you require additional information, please feel free to contact us.

It is very important to note that cancer can affect any dog of any breed at any age; however, the predisposition among breeds or families dogs to develop specific types of cancer underscores the importance of hereditary components in the development or progression of these diseases. We have worked to solidify the resemblance between naturally occurring tumors of dogs and people in the areas of lymphoma and leukemia, bone cancer, melanoma, and tumors of endothelial cells that line blood vessels (hemangiosarcomas). We believe this will have a visible and long-lasting impact on canine health by providing accurate and dependable information that can be used judiciously for breeding decisions and that will pave the way towards the development of advanced molecular therapies for canine cancer.

Below are lists of selected publications from our laboratory for each of these diseases. For more extensive details please see our list of publications. You can also contact our laboratory staff if you have questions or requests for more specific information.

Review and Opinion Articles
Breen M and Modiano JF. (2008) Shared pathogenesis of human and canine tumors - an inextricable link between cancer and evolution. Cancer Therapy, 6, 239-246

Khanna C, Lindblad-Toh K, Vail D, London C, Bergman P, Barber L, Breen M, Kitchell B, McNeil E, Modiano JF, Niemi S, Comstock K, Ostrander E, Westmoreland S, Withrow S. (2006) Dogs, cancer, translation and genomics: a novel comparative opportunity. Nat Biotech, 24 (9), 1065-1066.

Modiano JF, Breen M, Lana SE, Ehrhart N, Fosmire SP, Thomas R, Jubala CM, Lamerato-Kozicki AR, Ehrhart EJ, Schaack J, Duke RC, Cutter GC, Bellgrau D. (2006). Naturally occurring translational models for development of cancer gene therapy. Gene Ther Mol Biol, 10, 31-40.

Modiano JF, Ritt MG, Wojcieszyn J. (1999). The molecular basis of canine melanoma: Pathogenesis and trends in diagnosis and therapy. J Vet Intern Med 13, 163-174.

Modiano JF. (1998). Prognostic significance of malignant cell phenotypes in canine lymphoma (Editorial). Adv Vet Med Surg, 11(11), 1-2.

Lymphoma/Leukemia
 Breen M and Modiano JF. (2008) Evolutionarily conserved cytogenetic changes in hematologic malignancies of dogs and humans – Man and his best friend share more than companionship. Chromosome Res, 16(1), 145-154.

  • This is the first report that verifies identical pathognomonic chromosomal abnormalities exist in homologous Burkitt lymphoma, chronic myelogenous leukemia, and chromic lymphocytic leukemia of humans and dogs. Commentaries published in Nature 14:471, 2008 and Am J Vet Res 69:569, 2008.

Fosmire SP, Thomas R, Jubala CM, Wojcieszyn J, Valli VEO, Getzy DM, Smith TL, Gardner LA, Ritt MG, Bell JS, Freeman KP, Greenfield BE, Lana SE, Kisseberth WC, Helfand SC, Cutter GR, Breen M, Modiano JF. (2007) Inactivation of the p16 cyclin-dependent kinase inhibitor in high-grade canine non-Hodgkin T-cell lymphoma. Vet Pathol, 44(4), 467-478.

  • Multicenter study validated WHO classification of non-Hodgkin canine lymphomas based on loss of p16 and functional inactivation of Rb as biomarkers.

Modiano JF, Breen M, Valli VEO, Wojcieszyn JW, Cuter GR. (2007) Predictive value of p16 or Rb inactivation in a model of naturally occurring canine non-Hodgkin lymphoma. Leukemia, 21, 184-187.

  • Description of strengths of a model of naturally occurring non-Hodgkin lymphoma, particularly with respect to nodal, non-viral T cell tumors that can be readily studied in dogs, but are rare in humans. Documentation of the predictive value of Rb phosphorylation for response to standard of care and overall survival as outcome measure.

Modiano JF, Breen M, Burnett RC, Parker HG, Inusah S, Thomas R, Avery PR, Lindblad-Toh K, Ostrander EA, Cutter G, Avery AC. (2005). Distinct prevalence of B-cell and T-cell lymphoproliferative diseases among dog breeds indicates heritable risk. Cancer Res, 65, 5654-5661.

  • Use of naturally occurring canine lymphoproliferative diseases to explore heritable risk factors. Documentation of recent and ancestral traits that modulate risk and prevalence of B and T cell tumors. Commentary in Vet. Pathol 42: 677 – 678, 2005.

Jubala CM, Wojcieszyn J, Valli, VEO, Getzy DM, Fosmire SP, Coffey D, Bellgrau D, Modiano JF. (2005). Expression of CD20 in normal canine B cells and in canine non-Hodgkin’s lymphoma. Vet Pathol, 42, 468-476.

  • Identification of CD20 expression in normal and malignant canine B cells to validate diagnostic reagents and describe its expression as a possible target

Dickerson EB, Fosmire S, Padilla ML, Modiano JF, Helfand SC. (2002). Potential to target dysregulated interleukin-2 receptor expression in canine lymphoid and hematopoietic malignancies. J Immunother, 25, 36-45.

  • First report of the canine IL-2R alpha sequence and identification of IL-2R expression in canine hematopoietic tumors.

Helfand SC, Modiano JF, Moore PF, Soergel SA, MacWilliams PS, Dubielzig RD, Hank JA, Gelfand EW, Sondel PM. (1995). Functional IL-2 receptors are expressed on natural killer-like leukemic cells from a dog with cutaneous lymphoma. Blood 86, 636-645.

Hemangiosarcoma

Tamburini BA, Trapp S, Phang TL, Schappa JT, Hunter L, Modiano JF. (2009). Gene expression profiles of sporadic canine hemangiosarcoma are uniquely associated with breed. PLoSONE, 4(5):e5549.

  • First demonstration that genetic background (as defined by “breed”) influences the gene expression phenotype of otherwise indistinguishable tumors

Lamerato-Kozicki AR, Helm KM, Jubala CM, Modiano JF. (2006). Canine hemangiosarcoma originates from hematopoietic precursors with potential for endothelial differentiation. Exp Hematol, 34 (7), 870-878.

  • First report of confirmatory data for the cancer stem cell hypothesis in naturally occurring dog cancer; report of proof-of-concept for a non-invasive diagnostic test based on flow cytometric detection of malignant hemangiosarcoma cells in circulation.

Dickerson EB, Thomas R, Fosmire SP, Lamerato-Kozicki AR, Scott A, Bianco SR, Wojcieszyn J, Breen M, Helfand SC, Modiano JF. (2005). Mutations of phosphatase and tensin homolog deleted from chromosome 10 in canine hemangiosarcoma. Vet Pathol, 42, 618-632.

  • Characterization of novel mutations of the PTEN C-terminal domain in naturally-occurring canine endothelial tumors and of the significance of PTEN mutations in the progression of canine hemangiosarcoma

Fosmire SP, Dickerson EB, Scott A, Bianco SR, Pettengil M, Meylemans H, Padilla M, Frazer-Abel AA, Akhtar N, Getzy DM, Wojcieszyn J, Breen M, Helfand SC, Modiano JF. (2004). Canine malignant hemangiosarcoma as a model of primitive angiogenic endothelium. Lab Invest, 84, 562-572.

  • Description of novel reagents for study of angiogenesis and angiogenic tumors; first report of how nicotine affects endothelial cell precursors.

Osteosarcoma

Thomas R, Wang HJ, Tsai P-C, Langford C, Fosmire SP, Jubala CM, Getzy DM, Cutter GR, Modiano JF, Breen M. (2009). Influence of genetic background on tumor karyotypes: evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma. Chromosome Res, 17(3):365-377.

  • First demonstration that individual genetic backgrounds as defined by “breed” in dogs influence tumor karyotypes in a cancer with extensive genomic instability.

Melanoma and other cancers

Lin P-Y, Fosmire SP, Park S-H, Park J-Y, Baksh S, Modiano JF, Weiss RH. (2007). Attenuation of PTEN increases p21 stability and cytosolic localization: potential mechanism of chemotherapy resistance. Mol Cancer, 6, 16 (doi:10.1186/1476-4598-6-16).

  • Mechanistic determination of the reciprocal relationship between PTEN and p21 in cancer cells, and the possible role of p21 as an anti-apoptotic factor in PTEN-deficient cells.

Bianco SR, Sun J, Fosmire SP, Hance K, Padilla M, Ritt MG, Getzy D, Duke RC, Withrow S, Lana S, Matthiesen DT, Dow S, Bellgrau D, Cutter G, Helfand SC, Modiano JF. (2003). Enhancing anti-melanoma immune responses through apoptosis. Cancer Gene Ther, 10, 726-736.

  • Documentation of priming in antigen presenting cells by uptake of apoptotic cells, and the possibility to harness this in cancer immunotherapy.

Koenig A, Fosmire S, Bianco S, Wojcieszyn J, Modiano JF. (2002). Expression and significance of p53, Rb, p21/Waf-1, p16/Ink-4a, and PTEN tumor suppressors in canine melanoma. Vet Pathol, 39, 458-472.

  • Validation of the molecular similarity between the disease in dogs and humans. One of first reports to show reciprocal relationship between decreased PTEN expression and increased cytosolic p21

Koenig A, Weeks BR, Wojcieszyn J, Modiano JF. (2001). Expression of S100a, vimentin, NSE, and Melan A/MART-1 in seven canine melanoma cell lines and twenty-nine retrospective cases of canine melanoma. Vet Pathol, 38, 427-435.

  • Description of markers that are useful to diagnose canine melanoma, and validation of the phenotypic similarity between the disease in dogs and humans

Ritt MG, Wojcieszyn J, Smith R, III, Mayor J, Barton CL, Modiano JF. (2000). Sustained nuclear localization of p21/Waf-1 upon growth arrest induced by contact inhibition. Cancer Lett, 158, 73-84.

  • First description of how localization of p21 influences cell growth. Recent work, based partly on these observations, show that CYTOSOLIC p21 is an indicator of poor prognosis in various types of cancer

Modiano JF, Ritt MG, Wojcieszyn J, Smith R, III. (1999). Growth arrest of melanoma cells is differentially regulated by contact inhibition and serum deprivation. DNA Cell Biol, 18, 357-365.

  • First description of the role of p21 to mediate distinct signals leading to growth arrest

Ritt MG, Wojcieszyn J, Modiano JF. (1998). Functional loss of p21/Waf-1 in a case of benign canine multicentric melanoma. Vet Pathol 35, 94-101.